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1.
Endocrine ; 72(1): 132-139, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32720201

RESUMO

BACKGROUND AND AIM: Skeletal muscle (SM) has been shown as a target of thyroid hormones (THs). However, the status of TH signaling in aged SM remains unclear. This study aimed to explore the mechanism of TH signaling in SM of aging mice. METHODS: Thirty C57BL/6J male mice were divided into 6-, 15- and 22-month (6, 15 and 22M) groups according to different age. Physical parameters were evaluated by analytical balance, grip strength test and histological analysis. Thyroid function was detected by enzyme-linked immunosorbent assay. TH signaling was compared among the three groups by real-time PCR and western blotting analysis. RESULTS: p16, p21, and p53 mRNA levels in SM increased in age-dependent manner. The muscle weight and strength decreased in 22M group compared to 6 and 15M groups. Concentrations of thyroid hormones, including free triiodothyronine (FT3), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) in 22 M mice were not shown significant difference compared to 6M or 15M mice, although FT3 showed slightly decrease and TSH appeared a mild increase accompanying with age. mRNA levels of TH transporters, including MCT8 and MCT10, as well as iodothyronine deiodinase type 2 (DIO2) and type 3 (DIO3), were higher in 22M, while TH receptor α (TRα) mRNA and protein expression was lower in 22M, compared to the other groups. Type-I myosin heavy chain (MyHC I), MyHC IIx, and MyHC IIa were upregulated and Type-IIb MyHC (MyHC IIb) was downregulated in SM with advancing age. CONCLUSIONS: TH signaling in SM changes with aging.


Assuntos
Hormônios Tireóideos , Tireotropina , Envelhecimento , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético , Tiroxina , Tri-Iodotironina
2.
Toxicol Sci ; 177(2): 483-493, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32895711

RESUMO

PCB118, a 2,3',4,4',5-pentachlorobiphenyl, has been shown to destroy thyroidal ultrastructure and induce thyrocyte autophagy. Previously, we reported that PCB118 promoted autophagosome formation in vivo and in vitro, but more details remain to be revealed. To explore the underlying mechanism by which PCB118 regulates thyrocyte autophagy, Fischer rat thyroid cell line-5 (FRTL-5) cells were exposed to different doses of PCB118 at 0, 0.25, 2.5, and 25 nM for 0-48 h. Western blot analysis of autophagy-related proteins P62, BECLIN1, and LC3 demonstrated that PCB118 induced autophagy formation in dose- and time-dependent manner. Moreover, laser scanning confocal microscopy and flow cytometry showed PCB118 treatment led to time- and dose-dependent increase in intracellular calcium concentration ([Ca2+]i). Additionally, PCB118 promoted store-operated Ca2+ entry (SOCE) channel followed by significant increase of ORAI1 and STIM1 protein levels. On the other hand, PCB118 induced thyroidal autophagy via class III ß-tubulin (TUBB3)/death-associated protein kinase 2 (DAPK2)/myosin regulatory light chain (MRLC)/autophagy-related 9A (ATG9A) pathway in FRTL-5 cells. Pretreatment with SOCE inhibitor SKF96365 reduced cytosolic Ca2+, ORAI1, STIM1, and BECLIN1 levels as well as LC3 II/LC3 I ratio, while increased P62 expression. SKF96365 also inhibited TUBB3/DAPK2/MRLC/ATG9A pathway in FRTL-5 cells treated by PCB118. Our results provide evidence that PCB118 may induce thyroidal autophagy through TUBB3-related signaling pathway, and these effects are likely to be regulated by calcium influx via SOCE channel.


Assuntos
Cálcio , Células Epiteliais da Tireoide , Animais , Autofagia , Cálcio/metabolismo , Sinalização do Cálcio , Bifenilos Policlorados/toxicidade , Ratos , Transdução de Sinais , Células Epiteliais da Tireoide/metabolismo
3.
Aging Clin Exp Res ; 31(8): 1113-1120, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30367448

RESUMO

OBJECTIVES: With the increase in aging population worldwide, the incidence of sarcopenia is also increasing. Thyroid hormones are important regulators that can affect body composition and physical function. The association between thyroid hormone levels and sarcopenia in susceptible elderly euthyroid subjects remains unclear. In this study, we investigated the effect of thyroid hormone concentrations on body muscle mass, muscle strength and physical function related to sarcopenia in elderly Chinese euthyroid subjects. METHODS: A total of 94 elderly Chinese euthyroid subjects (73 men, 21 women) without medications or diseases which obviously affected muscle metabolism or thyroid function were included in our study. Concentrations of free triiodothyronine (FT3), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) were determined by immunoassays. Appendicular skeletal muscle mass (ASM) was assessed by dual-energy X-ray absorptiometry. Handgrip strength was measured using a Jamar hand dynamometer, and physical function was assessed by the Short Physical Performance Battery (SPPB). RESULTS: Muscle function, both handgrip strength and SPPB, was negatively associated with age, and FT3 demonstrated age-dependent decline. Pearson's correlation analysis showed positive associations of FT3 with ASM, handgrip strength and SPPB. Neither FT4 nor TSH was associated with these parameters of sarcopenia in euthyroid subjects. Significantly positive correlations between FT3 and ASM, handgrip strength and SPPB were also observed in multiple linear regression analysis adjusted for age, gender and BMI, while no significant correlations were found between FT4 or TSH and aforementioned four parameters of sarcopenia. Subjects with sarcopenia had lower level of FT3. CONCLUSIONS: Higher FT3 concentration within normal range was correlated to muscle mass and muscle function in elderly subjects.


Assuntos
Sarcopenia/diagnóstico , Glândula Tireoide/fisiologia , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Feminino , Força da Mão , Humanos , Modelos Lineares , Masculino , Análise Multivariada , Valores de Referência , Sarcopenia/fisiopatologia , Testes de Função Tireóidea , Tireotropina/sangue , Tiroxina/sangue , Tri-Iodotironina/sangue
4.
Toxicol Sci ; 149(2): 300-11, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26519956

RESUMO

Polychlorinated biphenyls (PCBs) are durable and widely distributed environmental contaminants that can compromise the normal functions of multiple organs and systems; one important mechanism is the induction of inflammatory disorders. In this study, we explored the influences of 2,3',4,4',5-pentachlorobiphenyl (PCB118) on inflammatory responses and its underlying mechanisms in the thyroid. Wistar rats were administered PCB118 intraperitoneally at 0, 10, 100, and 1000 µg/kg/d, 5 days a week for 13 weeks; rat thyroid FRTL-5 cells were treated with PCB118 (0, 0.25, 2.5, and 25 nM) for indicated time. Results revealed that PCB118 promoted the generation of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and intercellular adhesion molecule-1 (ICAM-1) in a time- and dose-related manner and decreased sodium/iodide symporter (NIS) protein expression. Moreover, stimulation with PCB118 resulted in the upregulation of the aryl hydrocarbon receptor (AhR)-responsive gene cytochrome P450 1A1 in FRTL-5 cells; whereas pretreatment with the AhR inhibitor α-naphthoflavone or AhR small interfering RNA (siRNA) suppressed AhR, CYP1A1, IL-6, and ICAM-1 and restored NIS expression. In vivo and in vitro studies also suggested that the c-Jun N-terminal kinase (JNK) pathway was activated on PCB118 exposure, and the experiments using siRNA for JNK partially blocked PCB118-induced upregulation of IL-6 and ICAM-1 and downregulation of NIS. Altogether, PCB118 stimulates production of IL-6, TNF-α, and ICAM-1 in the thyroid through AhR and JNK activations and subsequently interferes with NIS expression, resulting in the disruption of thyroid structure and function.


Assuntos
Inflamação/induzido quimicamente , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Bifenilos Policlorados/toxicidade , Receptores de Hidrocarboneto Arílico/fisiologia , Transdução de Sinais/efeitos dos fármacos , Glândula Tireoide/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Citocromo P-450 CYP1A1/genética , Molécula 1 de Adesão Intercelular/biossíntese , Interleucina-6/biossíntese , Masculino , Ratos , Ratos Wistar , Glândula Tireoide/patologia , Fator de Necrose Tumoral alfa/análise
5.
PLoS One ; 10(3): e0120133, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25789747

RESUMO

Polychlorinated biphenyls (PCBs) can severely interfere with multiple animals and human systems. To explore the molecular mechanisms underlying 2, 3', 4, 4', 5- pentachlorobiphenyl (PCB118)-induced thyroid dysfunction, Fischer rat thyroid cell line-5(FRTL-5) cells were treated with either different concentrations of PCB118 or dimethyl sulfoxide (DMSO). The effects of PCB118 on FRTL-5 cells viability and apoptosis were assessed by using a Cell Counting Kit-8 assay and apoptosis assays, respectively. Quantitative real-time polymerase chain reaction was used to quantify protein kinase B (Akt), Forkhead box protein O3a (FoxO3a), and sodium/iodide symporter (NIS) mRNA expression levels. Western blotting was used to detect Akt, phospho-Akt (p-Akt), FoxO3a, phospho-FoxO3a (p-FoxO3a), and NIS protein levels. Luciferase reporter gene technology was used to detect the transcriptional activities of FoxO3a and NIS promoters. The effects of the constitutively active Akt (CA-Akt) and dominant-negative Akt (DN-Akt) plasmids on p-Akt, p-FoxO3a, and NIS levels were examined in PCB118-treated FRTL-5 cells. The effects of FoxO3a siRNA on FoxO3a, p-FoxO3a, and NIS protein levels were examined in the PCB118-treated FRTL-5 cells. The effects of pcDNA3 (plsmid vectors designed for high-level stable and transient expression in mammalian host)-FoxO3a on NIS promoter activity were examined in the PCB118-treated FRTL-5 cells. Our results indicated that relatively higher PCB118 concentrations can inhibit cell viability in a concentration- and time-dependent manner. Akt, p-Akt, and p-FoxO3a protein or mRNA levels increased significantly in PCB118-treated groups and NIS protein and mRNA levels decreased considerably compared with the control groups. FoxO3a promoter activity increased significantly, whereas NIS promoter activity decreased. These effects on p-FoxO3a and NIS could be decreased by the DN-Akt plasmid, enhanced by the CA-Akt plasmid, and blocked by FoxO3a siRNA. The overexpressed FoxO3a could reduce NIS promoter activity. Our results suggested that PCB118 induces thyroid cell dysfunction through the Akt/FoxO3a/NIS signaling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Bifenilos Policlorados/toxicidade , Animais , Linhagem Celular , Dimetil Sulfóxido/farmacologia , Regulação para Baixo/efeitos dos fármacos , Proteína Forkhead Box O3 , Fatores de Transcrição Forkhead/antagonistas & inibidores , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Simportadores/genética , Simportadores/metabolismo , Glândula Tireoide/citologia , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/metabolismo , Regulação para Cima/efeitos dos fármacos
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