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1.
Nat Commun ; 12(1): 1341, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33637716

RESUMO

Hypoxia-inducible factor-1 (HIF-1) is a master driver of glucose metabolism in cancer cells. Here, we demonstrate that a HIF-1α anti-sense lncRNA, HIFAL, is essential for maintaining and enhancing HIF-1α-mediated transactivation and glycolysis. Mechanistically, HIFAL recruits prolyl hydroxylase 3 (PHD3) to pyruvate kinase 2 (PKM2) to induce its prolyl hydroxylation and introduces the PKM2/PHD3 complex into the nucleus via binding with heterogeneous nuclear ribonucleoprotein F (hnRNPF) to enhance HIF-1α transactivation. Reciprocally, HIF-1α induces HIFAL transcription, which forms a positive feed-forward loop to maintain the transactivation activity of HIF-1α. Clinically, high HIFAL expression is associated with aggressive breast cancer phenotype and poor patient outcome. Furthermore, HIFAL overexpression promotes tumor growth in vivo, while targeting both HIFAL and HIF-1α significantly reduces their effect on cancer growth. Overall, our results indicate a critical regulatory role of HIFAL in HIF-1α-driven transactivation and glycolysis, identifying HIFAL as a therapeutic target for cancer treatment.


Assuntos
Glicólise/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , RNA Longo não Codificante/metabolismo , Ativação Transcricional/fisiologia , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteínas de Transporte/metabolismo , Retroalimentação , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Hormônios Tireóideos/metabolismo
2.
Ecotoxicol Environ Saf ; 208: 111585, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33396108

RESUMO

Uranium is a radioactive element that is widely present in aquatic environment. However, limited knowledge is available about the effect of uranium on thyroid system, which plays a key role in the development of animals. In this study, zebrafish embryos were exposed to different environmentally relevant concentrations of uranium (2, 20 and 100 µg/L) for 120 h. The bioaccumulation, developmental toxicities, changes of thyroid hormones (THs) and key genes related to the hypothalamic-pituitary-thyroid (HPT) axis in larvae were analyzed after exposure. Results showed that uranium could bioaccumulate in zebrafish larvae, with the bioconcentration factors ranging from 49.6 to 523. Consequently, significant developmental toxicities and changes in locomotor activities were observed with a concentration-dependent manner. The levels of triiodothyronine (T3) levels in larvae were substantially decreased, whereas those of thyroxine (T4) were increased in fish bodies. The levels of THs were regulated by the negative feedback loops through HPT axis related genes, most of which (NIS, Deio1, Deio2, TRα, TSHß and UGT1ab) were significantly depressed after exposure to uranium. Our results suggest the potential toxicities and thyroid disruption of uranium on zebrafish, which would provide baseline data set for better understanding the impact of waterborne uranium on aquatic organisms and the associated mechanisms. This study also highlights the key role of thyroid disruption in the ecological risk assessment of uranium pollution.


Assuntos
Glândula Tireoide/efeitos dos fármacos , Hormônios Tireóideos/metabolismo , Urânio/toxicidade , Poluentes Radioativos da Água/toxicidade , Peixe-Zebra/fisiologia , Animais , Larva , Tiroxina , Tri-Iodotironina , Peixe-Zebra/crescimento & desenvolvimento , Proteínas de Peixe-Zebra/genética
3.
Ecotoxicol Environ Saf ; 208: 111720, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33396051

RESUMO

Fine particulate matter (PM2.5), a ubiquitous environmental pollutant, has been indicated to affect thyroid hormone (TH) homeostasis in women, but the detailed mechanism behind this effect remains unclear. The objective of this study was to evaluate the roles of the hypothalamic-pituitary-thyroid (HPT) axis and hepatic transthyretin in the thyroid-disrupting effects of PM2.5. Sprague Dawley rats were treated with PM2.5 (0, 15 and 30 mg/kg) by passive pulmonary inhalation for 49 days; and recovery experimental group rats were dosed with PM2.5 (30 mg/kg) for 35 days, and no treatment was done during the subsequent 14 days. PM2.5 was handled twice a day by passive pulmonary inhalation throughout the study. After treatment, pathological changes were analyzed by performing haemotoxylin and eosin staining, measuring levels of THs and urine iodine (UI) in serum, plasma, and urine samples using enzyme-linked immunoabsorbent assay, and expression of proteins in the hypothalamus, pituitary, thyroid, and liver tissues of rats were analyzed by immunohistochemistry and Western blotting. The levels of oxidative stress factors, such as reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (Gpx), and nuclear factor-kappa B (NF-κB) in female rats' plasma were also evaluated by ELISA. The results of these analyses revealed that PM2.5 treatment induced pathologic changes in rat thyroid and liver characterized by increased follicular cavity size and decreased amounts of follicular epithelial cells and fat vacuoles, respectively. Serum levels of triiodothyronine, thyroxine, and thyroid stimulating hormone were significantly decreased, plasma NF-κB level was increased and plasma redox state was unbalanced (enhanced ROS, MDA and Gpx levels; reduced SOD activities) in female rats treated with PM2.5 (P < 0.05). PM2.5 treatment suppressed the biosynthesis and biotransformation of THs by increasing sodium iodide symporter, thyroid transcription factor 1, thyroid transcription factor 2, and paired box 8 protein expression levels (P < 0.05). Additionally, thyroid stimulating hormone receptor and thyroid peroxidase levels were significantly decreased (P < 0.05). Both thyrotropin releasing hormone receptor and thyroid stimulating hormone beta levels were enhanced (P < 0.05). Moreover, transport of THs was inhibited due to reduced protein expression of hepatic transthyretin upon treatment with PM2.5. In summary, PM2.5 treatment could perturb TH homeostasis by affecting TH biosynthesis, biotransformation, and transport, affecting TH receptor levels, and inducing oxidative stress and inflammatory responses. Activation of the HPT axis and altered hepatic transthyretin levels therefore appear to play a crucial role in PM2.5-induced thyroid dysfunction.


Assuntos
Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Material Particulado/toxicidade , Pré-Albumina/metabolismo , Glândula Tireoide/efeitos dos fármacos , Hormônios Tireóideos/metabolismo , Animais , Feminino , Homeostase/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Material Particulado/química , Ratos , Ratos Sprague-Dawley , Receptores dos Hormônios Tireóideos/metabolismo , Glândula Tireoide/metabolismo , Glândula Tireoide/patologia
4.
Ecotoxicol Environ Saf ; 211: 111957, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33493726

RESUMO

Cadmium (Cd) is hazardous to human health and it is also highly detrimental to amphibian life. In this study, Bufo gargarizans larvae were exposed to environmentally relevant Cd concentrations of 5, 100 and 200 µg L-1 from Gosner stage (Gs) 26 to Gs 42 of metamorphic climax about 6 weeks. The results showed thyroid structural injuries and thyroid signaling disruption were induced by high Cd exposure (100 and 200 µg L-1). Moreover, tadpole skeleton including whole body, vertebrata, forelimb and hindlimb was developmentally delayed by high Cd exposure through downregulating the mRNA expressions of genes involved with skeletal ossification and growth pathway. Moreover, liver histopathological injuries were caused by high Cd exposure featured by hepatocytes malformation, nuclear degeneration and increasing melanomacrophage centers. Meanwhile, liver apoptosis rate showed on the rise in a dose-dependent way and Cd stimulated liver apoptosis by upregulating mRNA expressions of genes related to extrinsic and intrinsic apoptosis pathways. Furthermore, high Cd caused hepatic glucometabolism disorder by decreasing the genetic expressions associated with glycolysis and mitochondrial oxidative phosphorylation. In addition, liver lipid metabolism was disrupted by high Cd exposure through downregulating mRNA levels of genes related to fatty oxidation and upregulating mRNA levels of genes related to fatty acid synthesis. We suggested that Cd did great harm to tadpole health by disturbing thyroid function, skeletal growth, liver cell apoptosis signaling and hepatic energy metabolism pathway.


Assuntos
Bufonidae/fisiologia , Cádmio/toxicidade , Disruptores Endócrinos/toxicidade , Poluentes Ambientais/toxicidade , Hormônios Tireóideos/metabolismo , Animais , Apoptose , Bufonidae/metabolismo , Cádmio/metabolismo , Expressão Gênica , Humanos , Larva/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Oxirredução , RNA Mensageiro/metabolismo , Glândula Tireoide/metabolismo
5.
Int J Mol Sci ; 22(1)2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33466458

RESUMO

The thyroid gland is both a thyroid hormone (TH) generating as well as a TH responsive organ. It is hence crucial that cathepsin-mediated proteolytic cleavage of the precursor thyroglobulin is regulated and integrated with the subsequent export of TH into the blood circulation, which is enabled by TH transporters such as monocarboxylate transporters Mct8 and Mct10. Previously, we showed that cathepsin K-deficient mice exhibit the phenomenon of functional compensation through cathepsin L upregulation, which is independent of the canonical hypothalamus-pituitary-thyroid axis, thus, due to auto-regulation. Since these animals also feature enhanced Mct8 expression, we aimed to understand if TH transporters are part of the thyroid auto-regulatory mechanisms. Therefore, we analyzed phenotypic differences in thyroid function arising from combined cathepsin K and TH transporter deficiencies, i.e., in Ctsk-/-/Mct10-/-, Ctsk-/-/Mct8-/y, and Ctsk-/-/Mct8-/y/Mct10-/-. Despite the impaired TH export, thyroglobulin degradation was enhanced in the mice lacking Mct8, particularly in the triple-deficient genotype, due to increased cathepsin amounts and enhanced cysteine peptidase activities, leading to ongoing thyroglobulin proteolysis for TH liberation, eventually causing self-thyrotoxic thyroid states. The increased cathepsin amounts were a consequence of autophagy-mediated lysosomal biogenesis that is possibly triggered due to the stress accompanying intrathyroidal TH accumulation, in particular in the Ctsk-/-/Mct8-/y/Mct10-/- animals. Collectively, our data points to the notion that the absence of cathepsin K and Mct8 leads to excessive thyroglobulin degradation and TH liberation in a non-classical pathway of thyroid auto-regulation.


Assuntos
Autofagia/fisiologia , Catepsina K/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Simportadores/metabolismo , Tireoglobulina/metabolismo , Glândula Tireoide/metabolismo , Hormônios Tireóideos/metabolismo , Animais , Transporte Biológico , Catepsina L/metabolismo , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hipófise/metabolismo
6.
Ecotoxicol Environ Saf ; 208: 111617, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33396137

RESUMO

Nitrate (NO3-), a potential toxic nitrogenous compound to aquatic animals, is distributed in aquatic ecosystems worldwide. The aim of this study was to investigate the effects of different NO3- levels on growth performance, health status, and endocrine function of juvenile turbot (Scophthalmus maximus) in recirculating aquaculture systems (RAS). Fish were exposed to 0 mg/L (control, CK), 50 mg/L (low nitrate, LN), 200 mg/L (medium nitrate, MN), and 400 mg/L (high nitrate, HN) NO3-N for 60 d in experimental RAS. Cumulative survival (CS) was significantly decreased with increasing NO3- levels in LN, MN, and HN. The lowest CS was 35% in the HN group. Growth parameters, including absolute growth rate, specific growth rate, and feed conversion rate, were significantly different in HN compared with that in the CK. Histological survey of gills and liver revealed dose-dependent histopathological damage induced by NO3- exposure and significant differences in glutamate pyruvate transaminase and glutamate oxalate transaminase in MN and HN compared with that in the CK. The hepatosomatic index in HN was significantly higher than that in the CK. Additionally, NO3- significantly increased bioaccumulation in plasma in LN, MN, and HN compared to that in the CK. Significant decreases in hemoglobin and increases in methemoglobin levels indicated reduced oxygen-carrying capacity in HN. Additionally, qRT-PCR and enzyme-linked immunosorbent assay (ELISA) were developed to investigate key biomarkers involved in the GH/IGF-1, HPT, and HPI axes. Compared with that in the CK, the abundance of GH, GHRb, and IGF-1 was significantly lower in HN, whereas GHRa did not differ between treatments. The plasma T3 level significantly decreased in LN, MN, and HN and T4 significantly decreased in HN. The CRH, ACTH, and plasma cortisol levels were significantly upregulated in HN compared with that in the CK. We conclude that elevated NO3- exposure leads to growth retardation, impaired health status, and endocrine disorders in turbot and the NO3- level for juvenile turbot culture should not exceed 50 mg/L NO3-N in RAS. Our findings indicate that endocrine dysfunction of the GH/IGF-1, HPT, and HPI axes might be responsible for growth inhibition induced by NO3- exposure.


Assuntos
Aquicultura/métodos , Sistema Endócrino/efeitos dos fármacos , Linguados/crescimento & desenvolvimento , Nitratos/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Ecossistema , Sistema Endócrino/metabolismo , Brânquias/efeitos dos fármacos , Brânquias/patologia , Nível de Saúde , Fígado/efeitos dos fármacos , Fígado/patologia , Alimentos Marinhos , Hormônios Tireóideos/metabolismo
7.
Ecotoxicol Environ Saf ; 209: 111845, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33385677

RESUMO

The coexistence of nanoparticles and organic toxicants in the environment modifies pollutant bioavailability and toxicity. This study investigated the influence of silicon dioxide nanoparticles (n-SiO2) on the uptake of tetrabromobisphenol A (TBBPA) and its impact on the thyroid endocrine system in zebrafish larvae. Zebrafish (Danio rerio) embryos were exposed to TBBPA at different concentrations (50, 100, and 200 µg/L) alone or in combination with n-SiO2 (25 mg/L) until 120 h post-fertilization (hpf). Chemical measurements showed that both TBBPA and n-SiO2 were bioconcentrated in zebrafish larvae, and the uptake of TBBPA was enhanced by n-SiO2. Furthermore, zebrafish larvae exposed to 200 µg/L TBBPA alone exhibited significantly increased T4 contents and decreased T3 contents, whereas n-SiO2 treatment alone did not have a detectable effect. Furthermore, the thyroid hormone levels changed more upon treatment with 200 µg/L TBBPA combined with 25 mg/L n-SiO2 than upon TBBPA treatment alone. Alterations in gene transcription along the related hypothalamic-pituitary-thyroid (HPT) axis were observed, and expression of the binding and transport protein transthyretin (TTR) was significantly decreased for both TBBPA alone and co-exposure with n-SiO2. Thus, the current study demonstrates that n-SiO2, even at the nontoxic concentrations, increases thyroid hormone disruption in zebrafish larvae co-exposed to TBBPA by promoting its bioaccumulation and bioavailability.


Assuntos
Nanopartículas/toxicidade , Bifenil Polibromatos/metabolismo , Dióxido de Silício/toxicidade , Poluentes Químicos da Água/metabolismo , Animais , Sistema Endócrino/efeitos dos fármacos , Sistema Endócrino/metabolismo , Larva/efeitos dos fármacos , Bifenil Polibromatos/toxicidade , Glândula Tireoide/efeitos dos fármacos , Hormônios Tireóideos/metabolismo , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo , Peixe-Zebra/fisiologia
8.
Chemosphere ; 262: 128012, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33182161

RESUMO

Due to global restriction on perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), the use of long-chain perfluoroalkyl substances (PFASs, C > 8) and their environmental occurrences have increased. PFOS and PFOA have been known for thyroid disruption, however, knowledge is still limited on thyroid disrupting effects of long-chain PFASs (C > 10). In this study, two long-chain perfluorinated carboxylic acids (PFCAs), i.e., perfluoroundecanoic acid (PFUnDA) and perfluorotridecanoic acid (PFTrDA), were chosen and investigated for thyroid disrupting effects, using zebrafish embryo/larvae and rat pituitary cell line (GH3). For comparison, PFOA was also added as a test chemical and also investigated for its thyroid disruption potential. Following a 5 d exposure to PFTrDA, zebrafish larvae showed upregulation of the genes responsible for thyroid hormone synthesis (tshß, nkx2.1, nis, tpo, mct8) and (de)activation (dio1, dio2). In contrast, both PFUnDA and PFOA induced no regulatory changes except for upregulation of a thyroid metabolism related gene (ugt1ab). Morphological changes such as decreased eyeball size, increased yolk sac size, or deflated swim bladder, occurred following exposure to PFUnDA, PFTrDA, and PFOA. In GH3 cells, exposure to PFUnDA and PFTrDA upregulated Tshß gene, suggesting that these PFCAs increase thyroid hormone synthesis through stimulation by Tsh. In summary, both long-chain PFCAs could cause transcriptional changes of thyroid regulating genes that may lead to increased malformation of the zebrafish larvae, but the pathway of thyroid disruption appears to be different by the chain length. Confirmation and validation in adult fish following long term exposure are warranted.


Assuntos
Ácidos Decanoicos/toxicidade , Disruptores Endócrinos/toxicidade , Ácidos Graxos/toxicidade , Fluorcarbonetos/toxicidade , Hipófise/efeitos dos fármacos , Glândula Tireoide/efeitos dos fármacos , Hormônios Tireóideos/metabolismo , Peixe-Zebra/metabolismo , Animais , Linhagem Celular , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Expressão Gênica/efeitos dos fármacos , Larva/efeitos dos fármacos , Larva/metabolismo , Hipófise/metabolismo , Ratos , Glândula Tireoide/metabolismo , Hormônios Tireóideos/genética
9.
Ecotoxicol Environ Saf ; 209: 111783, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33383340

RESUMO

Decabromodiphenyl ether (BDE-209) is widely used as a flame retardant in many products like electronic equipments, plastics, furniture and textiles. BDE-209, a thyroid hormones (THs)-disrupting chemical, affects male reproductive health through altered THs status in mouse model. The present study was designed in continuation to our earlier work to elucidate whether early life exposure to BDE-209 has a long term potential risk to male reproductive health. This study, therefore, aimed to evaluate the effect of maternal BDE-209 exposure during lactation and to elucidate possible mechanism(s) of its action on male reproduction in adult Parkes mice offspring. Lactating female Parkes mice were orally gavaged with 500, and 700 mg/kg body weight of BDE-209 in corn oil from postnatal day (PND) 1 to PND 28 along with 6-propyl-2-thiouracil (PTU)-treated positive controls and vehicle-treated controls. Male pups of lactating dams were euthanized at PND 75. Maternal BDE-209 exposure during lactation markedly affected histoarchitecture of testis and testosterone production with concomitant down-regulation in the expression of various steroidogenic markers in adult offspring. Maternal exposure to BDE-209 during lactation also interfered with germ cell dynamics and oxidative status in testes of adult mice offspring. A decreased expression of connexin 43 and androgen receptor was also evident in testes of these mice offspring; further, number, motility and viability of spermatozoa were also adversely affected in these mice. The results thus provide evidences that maternal exposure to BDE-209 during lactation causes reproductive toxicity in adult mice offspring.


Assuntos
Retardadores de Chama/toxicidade , Éteres Difenil Halogenados/toxicidade , Espermatogênese/efeitos dos fármacos , Animais , Conexina 43/metabolismo , Feminino , Células Germinativas/efeitos dos fármacos , Lactação/efeitos dos fármacos , Masculino , Exposição Materna , Camundongos , Receptores Androgênicos/metabolismo , Espermatozoides/efeitos dos fármacos , Esteroides/metabolismo , Testículo/efeitos dos fármacos , Testosterona/metabolismo , Hormônios Tireóideos/metabolismo
10.
Life Sci ; 267: 118977, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33383053

RESUMO

AIMS: Severe cardiovascular diseases, such as myocardial infarction or heart failure, can alter thyroid hormone (TH) secretion and peripheral conversion, leading to low triiodothyronine (T3) syndrome. Accumulating evidence suggests that TH has protective properties against cardiovascular diseases and that treatment with TH can effectively reduce myocardial damage after myocardial infarction (MI). Our aim is to investigate the effect of T3 pretreatment on cardiac function and pathological changes in mice subjected to MI and the underlying mechanisms. MAIN METHODS: Adult male C57BL/6 mice underwent surgical ligation of the left anterior descending coronary artery (LAD) (or sham operation) to establish MI model. T3, BMS-754807 (inhibitor of insulin-like growth factor-1 receptor (IGF-1R)) or vehicle was administered before surgery. KEY FINDINGS: Compared with the MI group, the T3 pretreatment group exhibited significant attenuation of the myocardial infarct area, inhibition of cardiomyocyte apoptosis and fibrosis, and improved left ventricular function after MI. In addition, T3 exhibited an enhanced potency to stimulate angiogenesis and exert anti-inflammatory effects by reducing the levels of serum inflammatory cytokines after MI. However, all of these protective effects were inhibited by the IGF-1R inhibitor BMS-754807. Moreover, the protein expression of IGF-1/PI3K/AKT signaling-related proteins, such as IGF-1, IGF-1R, phosphorylated PI3K (p-PI3K) and p-AKT was significantly upregulated in MI mice that received T3 pretreatment, and BMS-754807 pretreatment blocked the upregulation of the expression of these signaling-related proteins. SIGNIFICANCE: T3 pretreatment can protect the heart against dysfunction post-MI, which may be mediated by the activation of the IGF-1/PI3K/AKT signaling pathway.


Assuntos
Infarto do Miocárdio/tratamento farmacológico , Hormônios Tireóideos/metabolismo , Tri-Iodotironina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Remodelamento Atrial/efeitos dos fármacos , Remodelamento Atrial/fisiologia , Cardiotônicos/metabolismo , Cardiotônicos/farmacologia , Fibrose , Insuficiência Cardíaca/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Hormônios Tireóideos/fisiologia , Tri-Iodotironina/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos
11.
Cell Death Dis ; 11(12): 1047, 2020 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-33311447

RESUMO

SEMG1 and SEMG2 genes belong to the family of cancer-testis antigens (CTAs), whose expression normally is restricted to male germ cells but is often restored in various malignancies. High levels of SEMG1 and SEMG2 expression are detected in prostate, renal, and lung cancer as well as hemoblastosis. However, the functional importance of both SEMGs proteins in human neoplasms is still largely unknown. In this study, by using a combination of the bioinformatics and various cellular and molecular assays, we have demonstrated that SEMG1 and SEMG2 are frequently expressed in lung cancer clinical samples and cancer cell lines of different origins and are negatively associated with the survival rate of cancer patients. Using the pull-down assay followed by LC-MS/MS mass-spectrometry, we have identified 119 proteins associated with SEMG1 and SEMG2. Among the SEMGs interacting proteins we noticed two critical glycolytic enzymes-pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA). Importantly, we showed that SEMGs increased the protein level and activity of both PKM2 and LDHA. Further, both SEMGs increased the membrane mitochondrial potential (MMP), glycolysis, respiration, and ROS production in several cancer cell lines. Taken together, these data provide first evidence that SEMGs can up-regulate the energy metabolism of cancer cells, exemplifying their oncogenic features.


Assuntos
Metabolismo Energético , Neoplasias/metabolismo , Proteínas Secretadas pela Vesícula Seminal/metabolismo , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Respiração Celular , Metabolismo Energético/genética , Regulação Neoplásica da Expressão Gênica , Glicólise , Células HEK293 , Humanos , Lactato Desidrogenase 5/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Potencial da Membrana Mitocondrial , Proteínas de Membrana/metabolismo , Modelos Biológicos , Neoplasias/genética , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Secretadas pela Vesícula Seminal/genética , Análise de Sobrevida , Hormônios Tireóideos/metabolismo , Resultado do Tratamento , Regulação para Cima/genética
12.
Medicine (Baltimore) ; 99(45): e23067, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33157965

RESUMO

Bisphenol A (BPA) is a well-known endocrine-disrupting chemical which can cause potential health risks and interfere with thyroid hormones through multiple avenues. This study aimed to evaluate the hotspots and emerging trends on BPA and thyroid hormones by using a bibliometric method.Publications related on BPA and thyroid hormones were downloaded from Science Citation Index-Expanded database. Annual outputs, high yield journals, countries, institutions, authors and their cited times were summarized. In addition, keywords co-occurrence, burst references and citation networks were bibliometric analyzed.From 2000 to 2019, 418 articles were published. Both of the Environment International and Environmental Health Perspectives, United States, Chinese Academy of Sciences and Antonia M. Calafat were the most recorded journals, countries, institutions and authors, respectively. The main research area was Toxicology. In addition of the retrieve term "bisphenol-a" and "thyroid-hormone", "in-vitro", "exposure" and "endocrine disruptors", were the hotspot keywords and "triclosan", "oxidative stress" and "united-states" were the most recent trends keywords. "Thyroid hormone action is disrupted by Bisphenol A as an antagonist" published on The Journal of Clinical Endocrinology & Metabolism by Kenji Moriyama in 2002 got both the highest burst score and citation score. Six groups were clustered and the mechanism of BPA's effect on thyroid hormones, and the exposure of BPA and potential risks in children and pregnant women were the two main large fields.The number of publications in the field of BPA and thyroid hormones has increased tremendously since 2000. The research hotspot ranged from mechanism researches in animal models to epidemiological studies. "Thyroid hormone action is disrupted by bisphenol A as an antagonist" of Kenji Moriyama provided important building blocks in the field. The impact of BPA on thyroid hormones, especially pregnant women and children, was the latest research frontiers and might be the future direction of this filed in the following years.


Assuntos
Compostos Benzidrílicos/efeitos adversos , Depuradores de Radicais Livres/efeitos adversos , Fenóis/efeitos adversos , Publicações/estatística & dados numéricos , Hormônios Tireóideos/metabolismo , Animais , Compostos Benzidrílicos/farmacologia , Bibliometria , Criança , Gerenciamento de Dados , Disruptores Endócrinos/efeitos adversos , Disruptores Endócrinos/farmacologia , Feminino , Depuradores de Radicais Livres/farmacologia , Humanos , Modelos Animais , Fenóis/farmacologia , Gravidez , Tiroxina/efeitos dos fármacos , Tri-Iodotironina/efeitos dos fármacos
13.
Ecotoxicol Environ Saf ; 205: 111338, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32956867

RESUMO

Lead (Pb) is well-recognized for its great hazards to human and wildlife health. It has negative influences on multiple organs and systems of birds. Especially, lead exposure caused adverse impacts on bird reproduction. In this study, one week old female Japanese quails were randomly allocated into four groups and each group was respectively fed with 0, 50 ppm, 500 ppm and 1000 ppm Pb in drinking water for 36 days to determine the effects of chronic lead exposure on ovarian development and function. The results showed that Pb did accumulate in the ovary and ovarian development was delayed by high dose lead exposure (500 ppm and 1000 ppm). Moreover, high Pb dosage induced ovarian histopathological damages characterized by granulosa cells disorganization, follicle atresia and interstitial cell degeneration. Meanwhile, the concentration of estradiol (E2) was significantly decreased and mRNA levels of genes involved with ovarian steroidogenesis were significantly down-regulated by high concentration Pb. In addition, Pb exposure caused increasing cell apoptosis and significant changes of the expression of genes involved with cell death in the ovary. High dose Pb exposure also inhibited thyroid hormone release and disrupted ovarian thyroid deiodination apart from causing thyroid histopathological injury such as follicular deformation and atrophy. The study indicated that Pb might cause ovarian malfunction by inducing ovary and thyroid microstructural damages, thyroid hormone and estrogen release inhibition and ovarian steroidogenesis disruption.


Assuntos
Coturnix/metabolismo , Poluentes Ambientais/toxicidade , Estradiol/metabolismo , Expressão Gênica/efeitos dos fármacos , Chumbo/toxicidade , Ovário/efeitos dos fármacos , Hormônios Tireóideos/metabolismo , Adolescente , Animais , Apoptose/efeitos dos fármacos , Coturnix/genética , Coturnix/crescimento & desenvolvimento , Relação Dose-Resposta a Droga , Poluentes Ambientais/metabolismo , Estradiol/genética , Feminino , Células da Granulosa/efeitos dos fármacos , Células da Granulosa/patologia , Humanos , Chumbo/metabolismo , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/patologia , Ovário/crescimento & desenvolvimento , Ovário/metabolismo , Ovário/patologia , Distribuição Aleatória , Reprodução/efeitos dos fármacos , Reprodução/genética , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/metabolismo , Glândula Tireoide/patologia , Hormônios Tireóideos/genética
14.
Ecotoxicology ; 29(9): 1431-1440, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32975733

RESUMO

Climate change and pollution are some of the greatest anthropogenic threats to wild animals. Transgenerational plasticity-when parental exposure to environmental stress leads to changes in offspring phenotype-has been highlighted as a potential mechanism to respond to various environmental and anthropogenic changes across taxa. Transgenerational effects may be mediated via multiple mechanisms, such as transfer of maternal hormones to eggs/foetus. However, sources of variation in hormone transfer are poorly understood in fish, and thus the first step is to characterise whether environmental challenges alter transfer of maternal hormones to eggs. To this end, we explored the population variation and environmental variation (in response to temperature and endocrine disrupting copper) in maternal thyroid hormone (TH), transfer to offspring in a common fish model species, the three-spined stickleback (Gasterosteus aculeatus) using multiple approaches: (i) We compared ovarian TH levels among six populations across a wide geographical range in the Baltic Sea, including two populations at high water temperature areas (discharge water areas of nuclear power plants) and we experimentally exposed fish to (ii) environmentally relevant heat stress and (iii) copper for 7 days. We found that populations did not differ in intraovarian TH levels, and short-term heat stress did not influence intraovarian TH levels. However, copper exposure increased both T4 and T3 levels in ovaries. The next step would be to evaluate if such alterations would lead to changes in offspring phenotype.


Assuntos
Cobre/toxicidade , Smegmamorpha/fisiologia , Hormônios Tireóideos/metabolismo , Poluentes Químicos da Água/toxicidade , Animais , Feminino , Resposta ao Choque Térmico/fisiologia , Ovário/metabolismo
15.
Rev. ORL (Salamanca) ; 11(3): 253-257, jul.-sept. 2020. tab
Artigo em Espanhol | IBECS | ID: ibc-197894

RESUMO

El estudio de la patología funcional tiroidea requiere de un adecuado conocimiento de los procesos implicados en la síntesis, secreción, transporte, metabolismo y regulación y mecanismo de acción de las hormonas tiroideas En el manejo inicial de la disfunción tiroidea, la interpretación de los valores de Tirotropina (TSH) y de las hormonas periféricas (T4 y T3 libre) nos permitirán saber si la etiología está en el tiroides o fuera del tiroides. OBJETIVO: exponer unos conocimientos básicos sobre la fisiología y las alteraciones funcionales de la glándula tiroides


The study of functional thyroid pathology requires an adequate knowledge of the processes involved in the synthesis, secretion, transport, metabolism and regulation and mechanism of action of thyroid hormones In the initial management of thyroid dysfunction, the interpretation of the values of Thyrotropin (TSH) and peripheral hormones (free T4 and T3) will let us know if the etiology is in the thyroid or outside the thyroid. OBJECTIVE: to expose some basic knowledge about the physiology and functional alterations of the thyroid gland


Assuntos
Humanos , Glândula Tireoide/fisiopatologia , Glândula Tireoide/patologia , Hormônios Tireóideos/biossíntese , Doenças da Glândula Tireoide/diagnóstico , Técnicas de Laboratório Clínico/métodos , Hormônios Tireóideos/metabolismo , Doenças da Glândula Tireoide/fisiopatologia
16.
Life Sci ; 258: 118190, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32777299

RESUMO

AIMS: Glycolysis is an important process for cervical carcinoma development. Previous studies have indicated that stress-induced phosphoprotein 1 (STIP1) is associated with development of multiple tumors. Nevertheless, the role and mechanism of STIP1 in glycolysis of cervical carcinoma remain unclear. MAIN METHODS: The association between STIP1 and survival probability and the correlation between STIP1 expression and pyruvate kinase M2 (PKM2) as well as lactate dehydrogenase isoform A (LDHA) levels in cervical carcinoma were analyzed via The Cancer Genome Atlas (TCGA). The expression of STIP1, PKM2, LDHA, and cytochrome c (Cyt C) was measured via western blot or quantitative reverse transcription polymerase chain reaction. Cell viability and apoptosis were examined via cell counting kit 8 and flow cytometry, respectively. Glycolysis was assessed via detection of glucose consumption and lactate production. The protein involved in the Wnt/ß-catenin pathway was measured via western blot. KEY FINDINGS: STIP1 abundance was elevated in cervical carcinoma cells. High expression of STIP1 indicated poor survival probability. Knockdown of STIP1 inhibited cervical carcinoma cell viability and promoted apoptosis. STIP1 expression was positively correlated with PKM2 and LDHA levels in cervical carcinoma. Silence of STIP1 inhibited glycolysis and decreased PKM2 and LDHA expression. Down-regulation of STIP1 repressed the Wnt/ß-catenin pathway. Overexpression of ß-catenin reversed the effect of STIP1 silence on viability, apoptosis, glycolysis, and levels of PKM2 and LDHA. SIGNIFICANCE: STIP1 knockdown suppressed glycolysis in cervical carcinoma by inhibiting PKM2 and LDHA expression and activation of the Wnt/ß-catenin pathway.


Assuntos
Proteínas de Transporte/metabolismo , Regulação para Baixo/genética , Glicólise , Proteínas de Choque Térmico/metabolismo , Lactato Desidrogenase 5/metabolismo , Proteínas de Membrana/metabolismo , Hormônios Tireóideos/metabolismo , Neoplasias do Colo do Útero/genética , Via de Sinalização Wnt , Apoptose , Linhagem Celular Tumoral , Sobrevivência Celular , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Proteínas de Choque Térmico/genética , Humanos , Modelos Biológicos , Neoplasias do Colo do Útero/patologia , Via de Sinalização Wnt/genética
17.
J Med Life ; 13(2): 219-224, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32742517

RESUMO

Periodontal disease is a chronic bacterial infection characterized by persistent inflammation, connective tissue breakdown, and alveolar bone destruction. The current study aimed to compare the connective tissue metabolism indices in rats with comorbidity-free periodontitis and in animals with periodontitis in a setting of hyper-and hypothyroidism. 12-14-week-old inbred white male rats (n=48) were included in the experiment. They were randomly divided into the following groups: control, animals with a model of periodontitis, animals with periodontitis in a setting of hyperthyroidism, animals with periodontitis in a setting of hypothyroidism. Serum levels of free thyroxine, free triiodothyronine, and thyroid-stimulating hormone were assayed using ELISA kits manufactured by Vector Best (Russia) to confirm the hyper- and hypothyroid status. Collagenolytic activity, the content of glycosaminoglycans, free hydroxyproline, and fucose, unbound with proteins in blood serum were assayed using the spectrophotometric method. We have found the increasing of collagenolytic activity by 46.1% (р<0.001), the content of free hydroxyproline by 74.1% (р<0.001), the content of glycosaminoglycans by 1.8 times (р<0.001), the content of fucose, unbound with proteins by 2.8 times (р<0.001) in rats with periodontitis vs. the control group. The development of periodontitis in a setting of thyroid dysfunction leads to an even more significant increase in the destruction of connective tissue, which is confirmed by a significant increase in the content of studied indices vs. euthyroid animals, both in hyperthyroidism and hypothyroidism.


Assuntos
Tecido Conjuntivo/metabolismo , Periodontite/complicações , Glândula Tireoide/fisiopatologia , Animais , Comorbidade , Masculino , Ratos , Hormônios Tireóideos/metabolismo
18.
Chemosphere ; 260: 127565, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32758781

RESUMO

The effects of fluoride on endocrine tissues has not been sufficiently explored to date. The current body of knowledge suggest significant effects of that mineral on reducing sex hormone levels, which may consequently impair fertility and disrupt puberty. The majority of studies confirm that sodium fluoride increases TSH levels and decreases the concentrations of T3 and T4 produced by the thyroid. Moreover, a correlation was observed between NaF and increased secretion of PTH by the parathyroid glands, without a significant impact on body calcium levels. Probably, fluoride may exert adverse effects on insulin levels, impairing pancreatic function and resulting in abnormal glucose tolerance. Observations also include decreased levels of cortisol secreted by the adrenal glands. In light of the few existing studies, the mechanism of fluoride toxicity on the endocrine system has been described.


Assuntos
Sistema Endócrino/efeitos dos fármacos , Fluoretos/farmacologia , Glândulas Suprarrenais/metabolismo , Animais , Fluoretos/efeitos adversos , Fluoretos/toxicidade , Humanos , Hidrocortisona/metabolismo , Insulina/análise , Glândulas Paratireoides/efeitos dos fármacos , Glândulas Paratireoides/metabolismo , Fluoreto de Sódio/farmacologia , Fluoreto de Sódio/toxicidade , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/metabolismo , Hormônios Tireóideos/metabolismo
19.
Aquat Toxicol ; 225: 105547, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32623180

RESUMO

Some chemicals in the environment disrupt thyroid hormone (TH) systems leading to alterations in organism development, but their effect mechanisms are poorly understood. In fish, this has been limited by a lack of fundamental knowledge on thyroid gene ontogeny and tissue expression in early life stages. Here we established detailed expression profiles for a suite of genes in the hypothalamic-pituitary-thyroid (HPT) axis of zebrafish (Danio rerio) between 24-120 h post fertilisation (hpf) and quantified their responses following exposure to 3,3',5-triiodo-L-thyronine (T3) using whole mount in situ hybridisation (WISH) and qRT-PCR (using whole-body extracts). All of the selected genes in the HPT axis demonstrated dynamic transcript expression profiles across the developmental stages examined. The expression of thyroid receptor alpha (thraa) was observed in the brain, gastrointestinal tract, craniofacial tissues and pectoral fins, while thyroid receptor beta (thrb) expression occurred in the brain, otic vesicles, liver and lower jaw. The TH deiodinases (dio1, dio2 and dio3b) were expressed in the liver, pronephric ducts and brain and the patterns differed depending on life stage. Both dio1 and dio2 were also expressed in the intestinal bulb (96-120 hpf), and dio2 expression occurred also in the pituitary (48-120 hpf). Exposure of zebrafish embryo-larvae to T3 (30 and 100 µg L-1) for periods of 48, 96 or 120 hpf resulted in the up-regulation of thraa, thrb, dio3b, thyroid follicle synthesis proteins (pax8) and corticotropin-releasing hormone (crhb) and down-regulation of dio1, dio2, glucuronidation enzymes (ugt1ab) and thyroid stimulating hormone (tshb) (assessed via qRT-PCR) and responses differed across life stage and tissues. T3 induced thraa expression in the pineal gland, pectoral fins, brain, somites, gastrointestinal tract, craniofacial tissues, liver and pronephric ducts. T3 enhanced thrb expression in the brain, jaw cartilage and intestine, while thrb expression was suppressed in the liver. T3 exposure suppressed the transcript levels of dio1 and dio2 in the liver, brain, gastrointestinal tract and craniofacial tissues, while dio2 signalling was also suppressed in the pituitary gland. Dio3b expression was induced by T3 exposure in the jaw cartilage, pectoral fins and brain. The involvement of THs in the development of numerous body tissues and the responsiveness of these tissues to T3 in zebrafish highlights their potential vulnerability to exposure to environmental thyroid-disrupting chemicals.


Assuntos
Tri-Iodotironina/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Hormônio Liberador da Corticotropina , Hipotálamo/efeitos dos fármacos , Larva/efeitos dos fármacos , Hipófise/efeitos dos fármacos , Glândula Tireoide/efeitos dos fármacos , Hormônios Tireóideos/metabolismo , Tironinas/metabolismo , Tironinas/farmacologia , Tireotropina , Peixe-Zebra/fisiologia , Proteínas de Peixe-Zebra/genética
20.
Nat Commun ; 11(1): 3614, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32681015

RESUMO

Larval metamorphosis and recruitment represent critical life-history transitions for most teleost fishes. While the detrimental effects of anthropogenic stressors on the behavior and survival of recruiting fishes are well-documented, the physiological mechanisms that underpin these patterns remain unclear. Here, we use pharmacological treatments to highlight the role that thyroid hormones (TH) play in sensory development and determining anti-predator responses in metamorphosing convict surgeonfish, Acanthurus triostegus. We then show that high doses of a physical stressor (increased temperature of +3 °C) and a chemical stressor (the pesticide chlorpyrifos at 30 µg L-1) induced similar defects by decreasing fish TH levels and affecting their sensory development. Stressor-exposed fish experienced higher predation; however, their ability to avoid predation improved when they received supplemental TH. Our results highlight that two different anthropogenic stressors can affect critical developmental and ecological transitions via the same physiological pathway. This finding provides a unifying mechanism to explain past results and underlines the profound threat anthropogenic stressors pose to fish communities.


Assuntos
Peixes/crescimento & desenvolvimento , Larva/crescimento & desenvolvimento , Praguicidas/toxicidade , Glândula Tireoide/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Clorpirifos/toxicidade , Poluição Ambiental/efeitos adversos , Metamorfose Biológica/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Glândula Tireoide/metabolismo , Hormônios Tireóideos/metabolismo
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