RESUMO
Thyroid hormone and thyroid hormone receptor (TR) play an essential role in metabolic regulation. However, the role of TR in adipogenesis has not been established. We reported previously that TR sumoylation is essential for TR-mediated gene regulation and that mutation of either of the two sites in TRα or any of the three sites in TRß reduces TR sumoylation. Here, we transfected TR sumoylation site mutants into human primary preadiocytes and the mouse 3T3L1 preadipocyte cell line to determine the role of TR sumoylation in adipogenesis. Reduced sumoylation of TRα or TRß resulted in fewer and smaller lipid droplets and reduced proliferation of preadipocytes. TR sumoylation mutations, compared with wild-type TR, results in reduced C/EBP expression and reduced PPARγ2 mRNA and protein levels. TR sumoylation mutants recruited NCoR and disrupted PPARγ-mediated perilipin1 (Plin1) gene expression, associated with impaired lipid droplet formation. Expression of NCoRΔID, a mutant NCoR lacking the TR interaction domain, partially "rescued" the delayed adipogenesis and restored Plin1 gene expression and adipogenesis. TR sumoylation site mutants impaired Wnt/ß-catenin signaling pathways and the proliferation of primary human preadipocytes. Expression of the TRß K146Q sumoylation site mutant down-regulated the essential genes required for canonical Wnt signal-mediated proliferation, including Wnt ligands, Fzds, ß-catenin, LEF1, and CCND1. Additionally, the TRß K146Q mutant enhanced the canonical Wnt signaling inhibitor Dickkopf-related protein 1 (DKK1). Our data demonstrate that TR sumoylation is required for activation of the Wnt canonical signaling pathway during preadipocyte proliferation and enhances the PPARγ signaling that promotes differentiation.
Assuntos
Adipócitos/citologia , Diferenciação Celular , Proliferação de Células , Receptores dos Hormônios Tireóideos/metabolismo , Sumoilação , Sequência de Bases , Células Cultivadas , Primers do DNA , Humanos , Mutação , PPAR gama/genética , PPAR gama/fisiologia , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , Receptores dos Hormônios Tireóideos/genéticaRESUMO
BACKGROUND AIMS: The contribution of amniotic fluid stem cells (AFSC) to tissue protection and regeneration in models of acute and chronic kidney injuries and lung failure has been shown in recent years. In the present study, we used a chemically induced mouse model of type 1 diabetes to determine whether AFSC could play a role in modulating ß-cell injury and restoring ß-cell function. METHODS: Streptozotocin-induced diabetic mice were given intracardial injection of AFSC; morphological and physiological parameters and gene expression profile for the insulin pathway were evaluated after cell transplantation. RESULTS: AFSC injection resulted in protection from ß-cell damage and increased ß-cell regeneration in a subset of mice as indicated by glucose and insulin levels, increased islet mass and preservation of islet structure. Moreover, ß-cell preservation/regeneration correlated with activation of the insulin receptor/Pi3K/Akt signaling pathway and vascular endothelial growth factor-A expression involved in maintaining ß-cell mass and function. CONCLUSIONS: Our results suggest a therapeutic role for AFSC in preserving and promoting endogenous ß-cell functionality and proliferation. The protective role of AFSC is evident when stem cell transplantation is performed before severe hyperglycemia occurs, which suggests the importance of early intervention. The present study demonstrates the possible benefits of the application of a non-genetically engineered stem cell population derived from amniotic fluid for the treatment of type 1 diabetes mellitus and gives new insight on the mechanism by which the beneficial effect is achieved.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Líquido Amniótico/química , Diabetes Mellitus Experimental/tratamento farmacológico , Células-Tronco/química , Injúria Renal Aguda/complicações , Injúria Renal Aguda/patologia , Líquido Amniótico/citologia , Animais , Terapia Baseada em Transplante de Células e Tecidos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Modelos Animais de Doenças , Humanos , Injeções , Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Pulmão/patologia , Camundongos , Regeneração , Transplante de Células-Tronco , Células-Tronco/citologiaRESUMO
We report the clinical characteristics and management of six patients with metastatic gastroentero-pancreatic neuroendocrine tumor (NET) presenting with severe hypercalcemia due to elevation of parathyroid hormone-related protein (PTHrP). All patients had histological confirmation of NET, five well-differentiated and one poorly differentiated. In 5 patients, hypercalcemia developed after years after the initial diagnosis of NET. One patient presented with concomitant elevation of PTHrP and intact parathyroid hormone (PTH) in the setting of multiple endocrine neoplasia 1 (MEN1). In all the other cases, PTH levels were low or undetectable. Management of malignant hypercalcemia due to PTHrP-producing NET is challenging, and optimal therapy depends on the extent of metastatic disease and the grade of malignancy. Aggressive tumor cytoreduction in addition to the systemic treatment modalities is frequently used to control disease progression and endocrine symptoms. To our knowledge, this is the largest series to date of hypercalcemia mediated by PTHrP-secreting NET.
Assuntos
Hipercalcemia/patologia , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Síndromes Paraneoplásicas/patologia , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Adulto , Terapia Combinada , Evolução Fatal , Feminino , Humanos , Hipercalcemia/etiologia , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/cirurgia , Neoplasias Pancreáticas/cirurgia , Síndromes Paraneoplásicas/etiologiaRESUMO
Injection of amniotic fluid stem cells ameliorates the acute phase of acute tubular necrosis in animals by promoting proliferation of injured tubular cells and decreasing apoptosis, but whether these stem cells could be of benefit in CKD is unknown. Here, we used a mouse model of Alport syndrome, Col4a5(-/-) mice, to determine whether amniotic fluid stem cells could modify the course of progressive renal fibrosis. Intracardiac administration of amniotic fluid stem cells before the onset of proteinuria delayed interstitial fibrosis and progression of glomerular sclerosis, prolonged animal survival, and ameliorated the decline in kidney function. Treated animals exhibited decreased recruitment and activation of M1-type macrophages and a higher proportion of M2-type macrophages, which promote tissue remodeling. Amniotic fluid stem cells did not differentiate into podocyte-like cells and did not stimulate production of the collagen IVa5 needed for normal formation and function of the glomerular basement membrane. Instead, the mechanism of renal protection was probably the paracrine/endocrine modulation of both profibrotic cytokine expression and recruitment of macrophages to the interstitial space. Furthermore, injected mice retained a normal number of podocytes and had better integrity of the glomerular basement membrane compared with untreated Col4a5(-/-) mice. Inhibition of the renin-angiotensin system by amniotic fluid stem cells may contribute to these beneficial effects. In conclusion, treatment with amniotic fluid stem cells may be beneficial in kidney diseases characterized by progressive renal fibrosis.
Assuntos
Rim/patologia , Nefrite Hereditária/terapia , Sistema Renina-Angiotensina/fisiologia , Transplante de Células-Tronco/métodos , Líquido Amniótico/citologia , Análise de Variância , Animais , Western Blotting , Células Cultivadas , Modelos Animais de Doenças , Progressão da Doença , Fibrose/patologia , Fibrose/terapia , Imuno-Histoquímica , Rim/fisiopatologia , Testes de Função Renal , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nefrite Hereditária/patologia , Podócitos/metabolismo , Distribuição Aleatória , Reação em Cadeia da Polimerase em Tempo Real , Estatísticas não ParamétricasRESUMO
Thyroid hormone receptor ß (THRB) is posttranslationally modified by small ubiquitin-like modifier (SUMO). We generated a mouse model with a mutation that disrupted sumoylation at lysine 146 (K146Q) and resulted in desumoylated THRB as the predominant form in tissues. The THRB K146Q mutant mice had normal serum thyroxine (T4), markedly elevated serum thyrotropin-stimulating hormone (TSH; 81-fold above control), and enlargement of both the pituitary and the thyroid gland. The marked elevation in TSH, despite a normal serum T4, indicated blunted feedback regulation of TSH. The THRB K146Q mutation altered the recruitment of transcription factors to the TSHß gene promoter, compared with WT, in hyperthyroidism and hypothyroidism. Thyroid hormone content (T4, T3, and rT3) in the thyroid gland of the THRB K146Q mice was 10-fold lower (per gram tissue) than control, despite normal TSH bioactivity. The expression of thyroglobulin and dual oxidase 2 genes in the thyroid was reduced and associated with modifications of cAMP response element-binding protein DNA binding and cofactor interactions in the presence of the desumoylated THRB. Therefore, thyroid hormone production had both TSH-dependent and TSH-independent components. We conclude that THRB sumoylation at K146 was required for normal TSH feedback regulation and TH synthesis in the thyroid gland, by a TSH-independent pathway.
Assuntos
Receptores beta dos Hormônios Tireóideos/metabolismo , Tireotropina/metabolismo , Tiroxina/metabolismo , Tri-Iodotironina/metabolismo , Animais , Masculino , Camundongos , Camundongos Transgênicos , Modelos Animais , Mutação , Hipófise/metabolismo , Regiões Promotoras Genéticas , Sumoilação/genética , Glândula Tireoide/metabolismo , Receptores beta dos Hormônios Tireóideos/genética , Tireotropina/sangue , Tiroxina/sangue , Tri-Iodotironina/sangueRESUMO
Thyroid hormone (TH) and thyroid hormone receptor (THR) regulate stem cell proliferation and differentiation during development, as well as during tissue renewal and repair in the adult. THR undergoes posttranslational modification by small ubiquitin-like modifier (SUMO). We generated the THRA (K283Q/K288R)-/- mouse model for in vivo studies and used human primary preadipocytes expressing the THRA sumoylation mutant (K283R/K288R) and isolated preadipocytes from mutant mice for in vitro studies. THRA mutant mice had reduced white adipose stores and reduced adipocyte cell diameter on a chow diet, compared to wild-type, and these differences were further enhanced after a high fat diet. Reduced preadipocyte proliferation in mutant mice, compared to wt, was shown after in vivo labeling of preadipocytes with EdU and in preadipocytes isolated from mice fat stores and studied in vitro. Mice with the desumoylated THRA had disruptions in cell cycle G1/S transition and this was associated with a reduction in the availability of cyclin D2 and cyclin-dependent kinase 2. The genes coding for cyclin D1, cyclin D2, cyclin-dependent kinase 2 and Culin3 are stimulated by cAMP Response Element Binding Protein (CREB) and contain CREB Response Elements (CREs) in their regulatory regions. We demonstrate, by Chromatin Immunoprecipitation (ChIP) assay, that in mice with the THRA K283Q/K288R mutant there was reduced CREB binding to the CRE. Mice with a THRA sumoylation mutant had reduced fat stores on chow and high fat diets and reduced adipocyte diameter.
Assuntos
Tecido Adiposo Branco/metabolismo , Sumoilação/fisiologia , Receptores alfa dos Hormônios Tireóideos/metabolismo , Receptores alfa dos Hormônios Tireóideos/fisiologia , Adipócitos/patologia , Adipócitos/fisiologia , Tecido Adiposo Branco/citologia , Animais , Proteína de Ligação a CREB/metabolismo , Proliferação de Células , Dieta Hiperlipídica/efeitos adversos , Humanos , Camundongos , Camundongos Mutantes , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/fisiologiaRESUMO
Thyroid hormone signaling plays an essential role in muscle development and function, in the maintenance of muscle mass, and in regeneration after injury, via activation of thyroid nuclear receptor alpha (THRA). A mouse model of resistance to thyroid hormone carrying a frame-shift mutation in the THRA gene (THRA-PV) is associated with accelerated skeletal muscle loss with aging and impaired regeneration after injury. The expression of nuclear orphan receptor chicken ovalbumin upstream promoter-factor II (COUP-TFII, or Nr2f2) persists during myogenic differentiation in THRA-PV myoblasts and skeletal muscle of aged THRA-PV mice and it is known to negatively regulate myogenesis. Here, we report that in murine myoblasts COUP-TFII interacts with THRA and modulates THRA binding to thyroid response elements (TREs). Silencing of COUP-TFII expression restores in vitro myogenic potential of THRA-PV myoblasts and shifts the mRNA expression profile closer to WT myoblasts. Moreover, COUP-TFII silencing reverses the transcriptomic profile of THRA-PV myoblasts and results in reactivation of pathways involved in muscle function and extracellular matrix remodeling/deposition. These findings indicate that the persistent COUP-TFII expression in THRA-PV mice is responsible for the abnormal muscle phenotype. In conclusion, COUP-TFII and THRA cooperate during post-natal myogenesis, and COUP-TFII is critical for the accelerated skeletal muscle loss with aging and impaired muscle regeneration after injury in THRA-PV mice.
Assuntos
Fator II de Transcrição COUP/metabolismo , Desenvolvimento Muscular , Doenças Musculares/etiologia , Receptores alfa dos Hormônios Tireóideos/metabolismo , Síndrome da Resistência aos Hormônios Tireóideos/etiologia , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mioblastos/metabolismo , Síndrome da Resistência aos Hormônios Tireóideos/complicações , Síndrome da Resistência aos Hormônios Tireóideos/metabolismo , TranscriptomaRESUMO
We present the case of a 71-year-old man with longstanding, previously well-controlled type 1 diabetes who developed acute hyperglycemia. His insulin requirements, via his insulin pump, increased to nearly five times his typical daily dose. The patient was admitted for evaluation and treatment and started on an insulin infusion. He had minimal insulin requirements with the insulin infusion. History revealed recent use of a super potent topical corticosteroid for a psoriasis flare. The patient was transitioned back to his insulin pump, using his prior to admission settings. He was advised to discontinue using his topical corticosteroid. He had no further hyperglycemic episodes. The clinical presentation is suggestive of corticosteroid-induced hyperglycemia, suggesting that clinically significant changes can occur even with short duration use, particularly with high potency steroids used. This is to our knowledge the first case reported in which the patient required a very significant amount of extra insulin (nearly five times his typical total daily dose) after using high potency topical steroid cream. This case highlights the potentially detrimental effect of topical corticosteroid use in patients with diabetes.
Assuntos
Hipotálamo , Glândula Tireoide , Humanos , Glândula Tireoide/metabolismo , Transdução de SinaisRESUMO
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 , DNA Metiltransferase 3A , Regulação da Expressão Gênica/efeitos dos fármacos , Neurônios/fisiologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , TranscriptomaRESUMO
BACKGROUND: Myopathic changes are commonly described in hypothyroid and hyperthyroid patients, including muscular atrophy and weakness. Satellite cells (SCs) play a major role in skeletal muscle maintenance and regeneration after injury. A mouse model of resistance to thyroid hormone-TRα1PV demonstrated impaired skeletal muscle regeneration after injury with significant reduction of SCs, suggesting that exhaustion of the SC pool contributes to the impaired regeneration. To test this hypothesis, SC activation and proliferation were analyzed in vivo in response to skeletal muscle injury and during aging. METHODS: SCs of TRα1PV male mice were analyzed four days after cardiotoxin-induced muscle injury, and they were compared to wild-type (WT) male animals. TRα-knockdown C2C12 myoblasts were injected into injured skeletal muscle, and four days after transplantation, the in vivo behavior was compared to control C2C12 myoblasts. Skeletal muscle regeneration was compared in younger and older TRα1PV and WT animals. RESULTS: The total number of SCs in skeletal muscle of TRα1PV mice was significantly lower than control, both before and shortly after muscle injury, with significant impairment of SC activation, consistent with SC pool exhaustion. TRα-knockdown myoblasts showed impaired in vivo proliferation and migration. TRα1PV mice had skeletal muscle loss and significant impairment in skeletal muscle regeneration with aging. This translated to a significant reduction of the SC pool with aging compared to WT mice. CONCLUSION: TRα plays an important role in the maintenance of the SC pool. Impaired skeletal muscle regeneration in TRα1PV mice is associated with insufficient SC activation and proliferation, as well as the progressive loss of the SC pool with aging. Regulation of the SC pool and SC proliferation provides a therapeutic target to enhance skeletal muscle regeneration and possibly slow age-associated sarcopenia.
Assuntos
Envelhecimento/metabolismo , Músculo Esquelético/metabolismo , Sarcopenia/metabolismo , Células Satélites de Músculo Esquelético/metabolismo , Receptores alfa dos Hormônios Tireóideos/metabolismo , Envelhecimento/genética , Animais , Proliferação de Células , Modelos Animais de Doenças , Masculino , Camundongos , Músculo Esquelético/lesões , Sarcopenia/genética , Receptores alfa dos Hormônios Tireóideos/genéticaRESUMO
Thyroid hormone plays an important role in brain development and adult brain function, and may influence neuronal recovery after Traumatic Brain Injury (TBI). We utilized both animal and cell culture models to determine the effects of thyroid hormone treatment, post TBI or during hypoxia, on genes important for neuronal survival and neurogenesis. We show that TBI in rats is associated with a reduction in serum thyroxine (T4) and triiodothyronine (T3). A single dose of levothyroxine (T4), one hour after injury, increased serum T4 and normalized serum T3 levels. Expression of genes important for thyroid hormone action in the brain, MCT8 and Type 2 deiodinase (Dio2) mRNA, diminished after injury, but were partially restored with T4 treatment. mRNA from the Type 3 deiodinase (Dio3) gene, which inactivates T4 to reverse T3 (rT3), was induced 2.7 fold by TBI, and further stimulated 6.7-fold by T4 treatment. T4 treatment significantly increased the expression of mRNA from Bcl2, VEGFA, Sox2 and neurotrophin, genes important for neuronal survival and recovery. The cortex, compared to the hippocampus and cerebellum, sustained the greatest injury and had the most significant change in gene expression as a result of injury and the greatest response to T4 treatment. We utilized hypoxia to study the effect of neuronal injury in vitro. Neuroblastoma cells were exposed to reduced oxygen tension, 0.2%, and were compared to cells grown at control oxygen levels of 21%. T3 treatment significantly increased hypoxia inducible factor (HIF)-2α protein, but not HIF-1α. In a hypoxia time course exposure, expression of hypoxia-mediated genes (VEGF, Enolase, HIF2α, c-Jun) peaked at least 8 h earlier with T3-treatment, compared to cells grown without T3. The early induction of these genes may promote cellular growth after injury. After hypoxic injury, T3 induced mRNA expression of the genes, KLF9 and hairless, important for T3-mediated brain function. The findings from both in vitro and in vivo studies support a role of thyroid hormone in activating pathways important for neuronal protection and promotion of neuronal recovery after injury.
Assuntos
Lesões Encefálicas/terapia , Neurônios/efeitos dos fármacos , Tiroxina/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Edema Encefálico/tratamento farmacológico , Lesões Encefálicas/sangue , Linhagem Celular , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Hipóxia Encefálica/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Neurogênese/genética , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Tiroxina/sangue , Tiroxina/farmacologia , Tri-Iodotironina/sangue , Tri-Iodotironina Reversa/metabolismoAssuntos
Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Albuterol/análogos & derivados , Cistite/induzido quimicamente , Hemorragia/induzido quimicamente , Doença Aguda , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Adulto , Albuterol/administração & dosagem , Albuterol/efeitos adversos , Albuterol/uso terapêutico , Asma/tratamento farmacológico , Tosse/tratamento farmacológico , Cistite/urina , Feminino , Hematúria/induzido quimicamente , Hematúria/urina , Hemorragia/urina , Humanos , Xinafoato de SalmeterolRESUMO
Thyroid hormone plays an essential role in myogenesis, the process required for skeletal muscle development and repair, although the mechanisms have not been established. Skeletal muscle develops from the fusion of precursor myoblasts into myofibers. We have used the C2C12 skeletal muscle myoblast cell line, primary myoblasts, and mouse models of resistance to thyroid hormone (RTH) α and ß, to determine the role of thyroid hormone in the regulation of myoblast differentiation. T3, which activates thyroid hormone receptor (TR) α and ß, increased myoblast differentiation whereas GC1, a selective TRß agonist, was minimally effective. Genetic approaches confirmed that TRα plays an important role in normal myoblast proliferation and differentiation and acts through the Wnt/ß-catenin signaling pathway. Myoblasts with TRα knockdown, or derived from RTH-TRα PV (a frame-shift mutation) mice, displayed reduced proliferation and myogenic differentiation. Moreover, skeletal muscle from the TRα1PV mutant mouse had impaired in vivo regeneration after injury. RTH-TRß PV mutant mouse model skeletal muscle and derived primary myoblasts did not have altered proliferation, myogenic differentiation, or response to injury when compared with control. In conclusion, TRα plays an essential role in myoblast homeostasis and provides a potential therapeutic target to enhance skeletal muscle regeneration.
Assuntos
Desenvolvimento Muscular , Músculo Esquelético/fisiologia , Mioblastos Esqueléticos/citologia , Regeneração , Receptores alfa dos Hormônios Tireóideos/agonistas , Tri-Iodotironina/metabolismo , Acetatos/farmacologia , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Resistência a Medicamentos , Mutação da Fase de Leitura , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Desenvolvimento Muscular/efeitos dos fármacos , Músculo Esquelético/citologia , Músculo Esquelético/lesões , Mioblastos Esqueléticos/efeitos dos fármacos , Mioblastos Esqueléticos/metabolismo , Fenóis/farmacologia , Interferência de RNA , Receptores alfa dos Hormônios Tireóideos/antagonistas & inibidores , Receptores alfa dos Hormônios Tireóideos/genética , Receptores alfa dos Hormônios Tireóideos/metabolismo , Receptores beta dos Hormônios Tireóideos/agonistas , Receptores beta dos Hormônios Tireóideos/genética , Receptores beta dos Hormônios Tireóideos/metabolismo , Tri-Iodotironina/análogos & derivados , Tri-Iodotironina/farmacologia , Via de Sinalização Wnt/efeitos dos fármacosRESUMO
BACKGROUND: Sudden death and increased prevalence of ventricular arrhythmias have already been described in acromegaly. Although late potentials (LPs) have been proved to be a new technique in detecting patients at risk for ventricular tachyarrhythmias its use in acromegaly is still unknown. METHODS: We studied 70 acromegalic patients [32 males, 38 females; age 49+/-12 years (mean+/-S.D.)] and 70 control subjects age- and sex-matched [(35 males and 35 females; 46+/-12 years (mean+/-S.D.)]. Besides hormonal tests, we performed the following cardiovascular investigations: ECG, 24-h ECG Holter monitoring, echocardiography, and signal-averaged ECG (SAECG) time-domain analysis. RESULTS: LPs occurrence was significantly higher in acromegalic patients as compared to the control group (22.9% vs. 2.9%; p=0.001). A greater duration of disease in patients with positive LPs compared to negative ones was pointed out (18 vs. 12 years; p=0.024). In the group of acromegalic patients with positive LPs we observed a significant association with premature ventricular complexes (PVCs) detected by means of 24-h Holter ECG recording (13 out of 15 patients: 86.7%; p=0.024). The positivity or negativity of LPs proved to be significantly associated with Lown scale PVC trends recorded by 24-h Holter ECG (p=0.014). In the group of patients with left ventricular hypertrophy a significant and pathological worsening of SAECG signals (QRS, LAS, RMS) was documented. CONCLUSIONS: We observed a higher prevalence of LPs in acromegaly which significantly correlated with Lown scale of PVCs.
Assuntos
Acromegalia/fisiopatologia , Potenciais de Ação , Taquicardia Ventricular/fisiopatologia , Acromegalia/sangue , Acromegalia/diagnóstico , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Morte Súbita Cardíaca/etiologia , Ecocardiografia , Eletrocardiografia Ambulatorial , Feminino , Hormônio do Crescimento Humano/metabolismo , Humanos , Hipertrofia Ventricular Esquerda/fisiopatologia , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Processamento de Sinais Assistido por Computador , Síncope/fisiopatologia , Taquicardia Ventricular/sangue , Taquicardia Ventricular/complicações , Taquicardia Ventricular/diagnóstico , Fatores de Tempo , Complexos Ventriculares Prematuros/fisiopatologiaRESUMO
Skeletal muscle is a plastic organ made by highly specialize fibers with specific and different structure, function and metabolism. Skeletal muscle fibers can adapt, change, recover/regenerate after injury in response to various stimulators including hormones. Thyroid hormones are important players in the homeostasis of several tissue including skeletal muscle and their genomic action mostly depend on the tissue T3 bioavailability and on the distribution of the thyroid receptor isoforms which act as transcription factors and are modulated by T3. Changing in contractile and metabolic proprieties of the muscle fibers has been described in experimental models of hyper and hypothyroidism. Animal models with disruption of thyroid hormone signaling showed different and specific skeletal muscle phenotypes. By focusing on thyroid hormone signaling in skeletal muscle homeostasis, we review T3 specific action on skeletal muscle development, postnatal growth, function and metabolism.
RESUMO
Bone marrow mesenchymal stem cells (BMSCs) have been shown to ameliorate diabetes in animal models. The mechanism, however, remains largely unknown. An unanswered question is whether BMSCs are able to differentiate into ß-cells in vivo, or whether BMSCs are able to mediate recovery and/or regeneration of endogenous ß-cells. Here we examined these questions by testing the ability of hBMSCs genetically modified to transiently express vascular endothelial growth factor (VEGF) or pancreatic-duodenal homeobox 1 (PDX1) to reverse diabetes and whether these cells were differentiated into ß-cells or mediated recovery through alternative mechanisms. Human BMSCs expressing VEGF and PDX1 reversed hyperglycemia in more than half of the diabetic mice and induced overall improved survival and weight maintenance in all mice. Recovery was sustained only in the mice treated with hBMSCs-VEGF. However, de novo ß-cell differentiation from human cells was observed in mice in both cases, treated with either hBMSCs-VEGF or hBMSCs- PDX1, confirmed by detectable level of serum human insulin. Sustained reversion of diabetes mediated by hBMSCs-VEGF was secondary to endogenous ß-cell regeneration and correlated with activation of the insulin/IGF receptor signaling pathway involved in maintaining ß-cell mass and function. Our study demonstrated the possible benefit of hBMSCs for the treatment of insulin-dependent diabetes and gives new insight into the mechanism of ß-cell recovery after injury mediated by hBMSC therapy.
Assuntos
Células da Medula Óssea/citologia , Células Secretoras de Insulina/fisiologia , Células-Tronco Mesenquimais/citologia , Regeneração/fisiologia , Adulto , Animais , Células da Medula Óssea/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/terapia , Proteínas de Homeodomínio/metabolismo , Humanos , Hiperglicemia/complicações , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Insulina/sangue , Células Secretoras de Insulina/enzimologia , Células Secretoras de Insulina/patologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/genética , Estreptozocina , Transativadores/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
PURPOSE OF REVIEW: Examine recent studies on the assessment of thyroid status in pregnancy, approach to thyroid testing, the spectrum of hypothyroidism in pregnancy, and strategies for thyroid replacement in women with known hypothyroidism. RECENT FINDINGS: Trimester-specific references range for thyroid-stimulating hormone (TSH) and free thyroxine in pregnancy must take into account iodine and thyroid autoantibody status, race, BMI, as well as other factors. Thyroid testing of only those pregnant women at increased risk for thyroid disease, case finding, will miss 30-80% of women with thyroid disease. Subclinical hypothyroidism is associated with an increasing number of adverse effects including infertility, miscarriage, preterm delivery, and breech presentation at birth. Many pregnant women with known hypothyroidism have an out-of-range TSH at the time of confirmed pregnancy. A variety of strategies are effective at keeping serum TSH normal during pregnancy including preconception increase in thyroxine, increase in thyroxine dose at the time pregnancy is confirmed, or making adjustments based on serum TSH monitoring. SUMMARY: Evaluation of thyroid status in pregnancy requires an understanding of pregnancy-associated changes in thyroid function tests and how they vary by trimester. The spectrum of hypothyroidism in pregnancy includes isolated thyroid peroxidase antibody positivity, isolated hypothyroxinemia, subclinical and overt hypothyroidism. These patterns, in some situations, may be related to iodine status, selenium status, or underlying thyroid disease. There are a variety of approaches to management of thyroxine replacement in known hypothyroid women at the time of pregnancy that are all effective at maintaining a normal range during pregnancy.