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1.
Thyroid ; 33(8): 983-996, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37140469

RESUMEN

Background: Low levels of triiodothyronine (T3) are common in patients with heart failure (HF). Our aim was to evaluate the effects of supplementation with low and replacement doses of T3 in an animal model of HF with preserved ejection fraction (HFpEF). Methods: We evaluated four groups: ZSF1 Lean (n = 8, Lean-Ctrl), ZSF1 Obese (rat model of metabolic-induced HFpEF, n = 13, HFpEF), ZSF1 Obese treated with a replacement dose of T3 (n = 8, HFpEF-T3high), and ZSF1 Obese treated with a low-dose of T3 (n = 8, HFpEF-T3low). T3 was administered in drinking water from weeks 13 to 24. The animals underwent anthropometric and metabolic assessments, echocardiography, and peak effort testing with maximum O2 consumption (VO2max) determination at 22 weeks, and a terminal hemodynamic evaluation at 24 weeks. Afterwhile myocardial samples were collected for single cardiomyocyte evaluation and molecular studies. Results: HFpEF animals showed lower serum and myocardial thyroid hormone levels than Lean-Ctrl. Treatment with T3 did not normalize serum T3 levels, but increased myocardial T3 levels to normal levels in the HFpEF-T3high group. Body weight was significantly decreased in both the T3-treated groups, comparing with HFpEF. An improvement in glucose metabolism was observed only in HFpEF-T3high. Both the treated groups had improved diastolic and systolic function in vivo, as well as improved Ca2+ transients and sarcomere shortening and relaxation in vitro. Comparing with HFpEF animals, HFpEF-T3high had increased heart rate and a higher rate of premature ventricular contractions. Animals treated with T3 had higher myocardial expression of calcium transporter ryanodine receptor 2 (RYR2) and α-myosin heavy chain (MHC), with a lower expression of ß-MHC. VO2max was not influenced by treatment with T3. Myocardial fibrosis was reduced in both the treated groups. Three animals died in the HFpEF-T3high group. Conclusions: Treatment with T3 was shown to improve metabolic profile, myocardial calcium handling, and cardiac function. While the low dose was well-tolerated and safe, the replacement dose was associated with increased heart rate, and increased risk of arrhythmias and sudden death. Modulation of thyroid hormones may be a potential therapeutic target in HFpEF; however, it is important to take into account the narrow therapeutic window of T3 in this condition.


Asunto(s)
Insuficiencia Cardíaca , Ratas , Animales , Insuficiencia Cardíaca/tratamiento farmacológico , Volumen Sistólico , Triyodotironina/farmacología , Triyodotironina/uso terapéutico , Calcio/metabolismo , Modelos Animales de Enfermedad , Obesidad/complicaciones
2.
Thyroid ; 33(4): 501-510, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36565029

RESUMEN

Introduction: Patients lacking functional monocarboxylate transporter 8 (MCT8), a highly specific thyroid hormone (TH) transporter, present severe psychomotor disabilities. MCT8 deficiency leads to peripheral hyperthyroidism and brain hypothyroidism, the latter due to impaired transport of TH across brain barriers. Available treatments for patients are limited and aim to overcome the limited TH transport across brain barriers. The use of TH analogues such as 3,3',5-triiodothyroacetic acid (TRIAC) that do not require MCT8 to cross the cellular membranes is considered a potential therapy for MCT8 deficiency. Previous studies have shown that systemic administration of TRIAC at therapeutic doses does not increase TRIAC content in the brain, while intracerebroventricular (ICV) administration of therapeutic doses of TRIAC increases TRIAC content in the brain but does not mediate thyromimetic effects. In view of this, we hypothesize that ICV administration of high doses of TRIAC can mediate thyromimetic effects in the brain without worsening the brain hypothyroidism or peripheral hyperthyroidism of patients. Methods: We administered 400 ng/g of body weight per day of ICV TRIAC in a mouse model of MCT8 deficiency: Mct8-/y and deiodinase 2 (Dio2)-/- double knockout mice. The effects of this treatment on TH and TRIAC levels/content in blood and tissues were determined by radioimmunoassay and effects on TH-regulated genes were assessed by real time-quantitative polymerase chain reaction in peripheral and central tissues. Results: ICV administration of high doses of TRIAC ameliorated the peripheral hyperthyroidism. In the brain, this treatment did not further aggravate brain hypothyroidism and increased TRIAC content in several brain regions; however, only moderate thyromimetic activity was observed in restricted brain areas. Conclusion: Administration of high doses of TRIAC by ICV delivery at juvenile stages in a mouse model of MCT8 deficiency is effective in normalizing peripheral hyperthyroidism but exerts minimal thyromimetic activity in the brain.


Asunto(s)
Hipertiroidismo , Hipotiroidismo , Simportadores , Animales , Ratones , Simportadores/genética , Triyodotironina , Hormonas Tiroideas , Encéfalo , Hipertiroidismo/tratamiento farmacológico , Hipotiroidismo/tratamiento farmacológico , Ratones Noqueados , Modelos Animales de Enfermedad , Transportadores de Ácidos Monocarboxílicos/genética
3.
Front Physiol ; 13: 1017381, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36467699

RESUMEN

Thyroid hormones (THs) play a major role regulating energy balance and brown adipose tissue (BAT) thermogenesis, as well as body temperature, as shown in hyperthyroid patients. However, the current landscape of preclinical thyroid hormone models is complex. For example, while rats become catabolic after TH administration, mice gain weight; so, these differences in species need to be analyzed in detail and specially whether temperature could be a factor. Here, we aimed to investigate the effect of environmental temperature on those actions. Rats were subcutaneously treated with L-thyroxine (T4) or stereotaxically within the ventromedial nucleus of the hypothalamus (VMH) with triiodothyronine (T3) and housed at 23°C, 4°C or 30°C; energy balance, BAT thermogenesis and AMP-activated protein kinase (AMPK) in the VMH were analyzed. Our data showed that the effect of both systemic T4 of central T3 on energy balance and BAT thermogenesis was dependent upon environmental temperature. This evidence is of interest in the design of experimental settings highlighting the species-specific metabolic actions of THs, and in understanding its physiological role in the adaptation to temperature.

4.
Neurobiol Dis ; 174: 105896, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36243247

RESUMEN

Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency.


Asunto(s)
Transportadores de Ácidos Monocarboxílicos , Simportadores , Animales , Ratones , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Simportadores/genética , Simportadores/metabolismo , Sistemas CRISPR-Cas , Hormonas Tiroideas/metabolismo , Modelos Animales de Enfermedad , Mamíferos/metabolismo
5.
PLoS Genet ; 18(6): e1010224, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35666718

RESUMEN

How cell to cell interactions control local tissue growth to attain a species-specific organ size is a central question in developmental biology. The Drosophila Neural Cell Adhesion Molecule, Fasciclin 2, is expressed during the development of neural and epithelial organs. Fasciclin 2 is a homophilic-interaction protein that shows moderate levels of expression in the proliferating epithelia and high levels in the differentiating non-proliferative cells of imaginal discs. Genetic interactions and mosaic analyses reveal a cell autonomous requirement of Fasciclin 2 to promote cell proliferation in imaginal discs. This function is mediated by the EGFR, and indirectly involves the JNK and Hippo signaling pathways. We further show that Fasciclin 2 physically interacts with EGFR and that, in turn, EGFR activity promotes the cell autonomous expression of Fasciclin 2 during imaginal disc growth. We propose that this auto-stimulatory loop between EGFR and Fasciclin 2 is at the core of a cell to cell interaction mechanism that controls the amount of intercalary growth in imaginal discs.


Asunto(s)
Proteínas de Drosophila , Discos Imaginales , Animales , Proliferación Celular/genética , Drosophila/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Receptores ErbB/genética , Receptores de Péptidos de Invertebrados/genética , Alas de Animales
6.
Nutrients ; 13(12)2021 Nov 24.
Artículo en Inglés | MEDLINE | ID: mdl-34959756

RESUMEN

Besides their direct effects on peripheral metabolic tissues, thyroid hormones (TH) act on the hypothalamus to modulate energy homeostasis. However, since most of the hypothalamic actions of TH have been addressed in studies with direct central administration, the estimation of the relative contribution of the central vs. peripheral effects in physiologic conditions of peripheral release (or administration) of TH remains unclear. In this study we used two different models of peripherally induced hyperthyroidism (i.e., T4 and T3 oral administration) to assess and compare the serum and hypothalamic TH status and relate them to the metabolic effects of the treatment. Peripheral TH treatment affected feeding behavior, overall growth, core body temperature, body composition, brown adipose tissue (BAT) morphology and uncoupling protein 1 (UCP1) levels and metabolic activity, white adipose tissue (WAT) browning and liver metabolism. This resulted in an increased overall uncoupling capacity and a shift of the lipid metabolism from WAT accumulation to BAT fueling. Both peripheral treatment protocols induced significant changes in TH concentrations within the hypothalamus, with T3 eliciting a downregulation of hypothalamic AMP-activated protein kinase (AMPK), supporting the existence of a central action of peripheral TH. Altogether, these data suggest that peripherally administered TH modulate energy balance by various mechanisms; they also provide a unifying vision of the centrally mediated and the direct local metabolic effect of TH in the context of hyperthyroidism.


Asunto(s)
Proteínas Quinasas Activadas por AMP/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Hipertiroidismo/metabolismo , Hipotálamo/metabolismo , Hormonas Tiroideas/administración & dosificación , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Animales , Modelos Animales de Enfermedad , Hipertiroidismo/inducido químicamente , Masculino , Ratones , Ratones Endogámicos C57BL
7.
Nat Commun ; 12(1): 5274, 2021 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-34489410

RESUMEN

The classical dogma states that brown adipose tissue (BAT) plays a major role in the regulation of temperature in neonates. However, although BAT has been studied in infants for more than a century, the knowledge about its physiological features at this stage of life is rather limited. This has been mainly due to the lack of appropriate investigation methods, ethically suitable for neonates. Here, we have applied non-invasive infrared thermography (IRT) to investigate neonatal BAT activity. Our data show that BAT temperature correlates with body temperature and that mild cold stimulus promotes BAT activation in newborns. Notably, a single short-term cold stimulus during the first day of life improves the body temperature adaption to a subsequent cold event. Finally, we identify that bone morphogenic protein 8B (BMP8B) is associated with the BAT thermogenic response in neonates. Overall, our data uncover key features of the setup of BAT thermogenesis in newborns.


Asunto(s)
Tejido Adiposo Pardo/fisiología , Temperatura Corporal/fisiología , Proteínas Morfogenéticas Óseas/sangre , Peso al Nacer , Glucemia/análisis , Frío , Factores de Crecimiento de Fibroblastos/sangre , Hormonas/sangre , Humanos , Recién Nacido , Termogénesis/fisiología
8.
PLoS One ; 15(7): e0236113, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32687511

RESUMEN

Loss of function mutations in the gene encoding the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to severe neurodevelopmental defects in humans associated with a specific thyroid hormone phenotype manifesting high serum 3,5,3'-triiodothyronine (T3) and low thyroxine (T4) levels. Patients present a paradoxical state of peripheral hyperthyroidism and brain hypothyroidism, this last one most likely arising from impaired thyroid hormone transport across the brain barriers. The administration of thyroid hormones by delivery pathways that bypass the brain barriers, such as the intranasal delivery route, offers the possibility to improve the neurological defects of MCT8-deficient patients. In this study, the thyroid hormones T4 and T3 were administrated intranasally in different mouse models of MCT8 deficiency. We have found that, under the present formulation, intranasal administration of thyroid hormones does not increase the content of thyroid hormones in the brain and further raises the peripheral thyroid hormone levels. Our data suggests intranasal delivery of thyroid hormones is not a suitable therapeutic strategy for MCT8 deficiency, although alternative formulations could be considered in the future to improve the nose-to-brain transport.


Asunto(s)
Transportadores de Ácidos Monocarboxílicos/deficiencia , Simportadores/deficiencia , Hormonas Tiroideas/administración & dosificación , Hormonas Tiroideas/farmacología , Administración Intranasal , Animales , Encéfalo/citología , Ratones , Transportadores de Ácidos Monocarboxílicos/genética , Mutación , Transducción de Señal/efectos de los fármacos , Simportadores/genética , Hormonas Tiroideas/sangre
9.
Front Neurosci ; 14: 380, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32410949

RESUMEN

Allan-Herndon-Dudley syndrome is a rare disease caused by inactivating mutations in the SLC16A2 gene, which encodes the monocarboxylate transporter 8 (MCT8), a transmembrane transporter specific for thyroid hormones (T3 and T4). Lack of MCT8 function produces serious neurological disturbances, most likely due to impaired transport of thyroid hormones across brain barriers during development resulting in severe brain hypothyroidism. Patients also suffer from thyrotoxicity in other organs due to the presence of a high concentration of T3 in the serum. An effective therapeutic strategy should restore thyroid hormone serum levels (both T3 and T4) and should address MCT8 transporter deficiency in brain barriers and neural cells, to enable the access of thyroid hormones to target neural cells. Unfortunately, targeted therapeutic options are currently scarce and their effect is limited to an improvement in the thyrotoxic state, with no sign of any neurological improvement. The use of thyroid hormone analogs such as TRIAC, DITPA, or sobetirome, that do not require MCT8 to cross cell membranes and whose controlled thyromimetic activity could potentially restore the normal function of the affected organs, are being explored to improve the cerebral availability of these analogs. Other strategies aiming to restore the transport of THs through MCT8 at the brain barriers and the cellular membranes include gene replacement therapy and the use of pharmacological chaperones. The design of an appropriate therapeutic strategy in combination with an early diagnosis (at prenatal stages), will be key aspects to improve the devastating alterations present in these patients.

10.
PLoS One ; 14(12): e0226017, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31809508

RESUMEN

Patients lacking the thyroid hormone (TH) transporter MCT8 present abnormal serum levels of TH: low thyroxine and high triiodothyronine. They also have severe neurodevelopmental defects resulting from cerebral hypothyroidism, most likely due to impaired TH transport across the brain barriers. The use of TH analogs, such as triiodothyroacetic acid (TRIAC), that can potentially access the brain in the absence of MCT8 and restore at least a subset of cerebral TH actions could improve the neurological defects in these patients. We hypothesized that direct administration of TRIAC into the brain by intracerebroventricular delivery to mice lacking MCT8 could bypass the restriction at the brain barriers and mediate TH action without causing hypermetabolism. We found that intracerebroventricular administration of therapeutic doses of TRIAC does not increase further plasma triiodothyronine or further decrease plasma thyroxine levels and does not alter TH content in the cerebral cortex. Although TRIAC content increased in the brain, it did not induce TH-mediated actions on selected target genes. Our data suggest that intracerebroventricular delivery of TRIAC has the ability to target the brain in the absence of MCT8 and should be further investigated to address its potential therapeutic use in MCT8 deficiency.


Asunto(s)
Corteza Cerebral/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Simportadores/genética , Hormonas Tiroideas/metabolismo , Triyodotironina/análogos & derivados , Animales , Femenino , Infusiones Intraventriculares , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transportadores de Ácidos Monocarboxílicos/deficiencia , Simportadores/deficiencia , Hormonas Tiroideas/química , Tiroxina/sangre , Triyodotironina/administración & dosificación , Triyodotironina/sangre
11.
Thyroid ; 29(11): 1669-1682, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31359845

RESUMEN

Background: Mutations in the thyroid hormone (TH) transporter monocarboxylate transporter 8 (MCT8) lead to peripheral hyperthyroidism and profound psychomotor alterations in humans. Mice lacking Mct8 present peripheral hyperthyroidism but no gross neurological abnormalities due to brain compensatory mechanisms involving the enzyme deiodinase type 2 (Dio2). Methods: Here we have analyzed the endocrine and neurologic phenotype of mice lacking both Mct8 and Dio2 at three and six months of age. Thyroxine (T4) and 3,5,3' triiodothyronine (T3) levels/content were measured by specific radioimmunoassays; motor skill performance was evaluated by the footprint, rotarod, four limb hanging wire, and balance beam tests; and brain histological analysis was performed by immunostaining for neurofilament and parvalbumin. Results: We have found that this mouse model presents peripheral hyperthyroidism and brain hypothyroidism. Interestingly, the severity of the brain hypothyroidism seems permanent and varies across regions, with the striatum being a particularly affected area. We have also found brain alterations at the histological level compatible with TH deficiency and impaired motor skills. Conclusions: These findings indicate the potential of Mct8/Dio2-deficient mice to represent a model for human MCT8 deficiency, to understand the mechanisms underlying its pathophysiology, and ultimately design therapeutic interventions for human patients.


Asunto(s)
Encefalopatías/genética , Yoduro Peroxidasa/genética , Transportadores de Ácidos Monocarboxílicos/genética , Destreza Motora , Enfermedades del Sistema Nervioso/genética , Simportadores/genética , Hormonas Tiroideas/metabolismo , Animales , Encefalopatías/patología , Encefalopatías/psicología , Modelos Animales de Enfermedad , Femenino , Yoduro Peroxidasa/deficiencia , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transportadores de Ácidos Monocarboxílicos/deficiencia , Desempeño Psicomotor , Simportadores/deficiencia , Glándula Tiroides/patología , Tiroxina/sangre , Triyodotironina/sangre , Yodotironina Deyodinasa Tipo II
12.
Thyroid ; 28(9): 1211-1220, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29845892

RESUMEN

BACKGROUND: Loss of function mutations in the thyroid hormone (TH)-specific cell membrane transporter, the monocarboxylate transporter 8 (MCT8), lead to profound psychomotor retardation and abnormal TH serum levels, with low thyroxine (T4) and high triiodothyronine (T3). Several studies point to impaired TH transport across brain barriers as a crucial pathophysiological mechanism resulting in cerebral hypothyroidism. Treatment options for MCT8-deficient patients are limited and are focused on overcoming the brain barriers. The aim of this study was to evaluate the ability of the TH analog sobetirome and its prodrug Sob-AM2 to access the brain and exert thyromimetic actions in the absence of Mct8. METHODS: Juvenile wild-type (Wt) mice and mice lacking Mct8 and deiodinase type 2 (Mct8/Dio2KO) were treated systemically with daily injections of vehicle, 1 mg of sobetirome/kg body weight/day, or 0.3 mg of Sob-AM2/kg body weight/day for seven days. Sobetirome content was measured using liquid chromatography-tandem mass spectrometry, and T4 and T3 levels by specific radioimmunoassays. The effect of sobetirome treatment in the expression of T3-dependent genes was measured in the heart, liver, and cerebral cortex by real-time polymerase chain reaction. RESULTS: Sob-AM2 treatment in Mct8/Dio2KO animals led to 1.8-fold more sobetirome content in the brain and 2.5-fold less in plasma in comparison to the treatment with the parent drug sobetirome. Both sobetirome and Sob-AM2 treatments in Mct8/Dio2KO mice greatly decreased plasma T4 and T3 levels. Dio1 and Ucp2 gene expression was altered in the liver of Mct8/Dio2KO mice and was not affected by the treatments. In the heart, Hcn2 but not Atp2a2 expression was increased after treatment with the analogs. Interestingly, both sobetirome and Sob-AM2 treatments increased the expression of several T3-dependent genes in the brain such as Hr, Abcd2, Mme, and Flywch2 in Mct8/Dio2KO mice. CONCLUSIONS: Sobetirome and its amide prodrug Sob-AM2 can access the brain in the absence of Mct8 and exert thyromimetic actions modulating the expression of T3-dependent genes. At the peripheral level, the administration of these TH analogs results in the depletion of circulating T4 and T3. Therefore, sobetirome and Sob-AM2 have the potential to address the cerebral hypothyroidism and the peripheral hyperthyroidism characteristic of MCT8 deficiency.


Asunto(s)
Acetatos/farmacología , Encéfalo/efectos de los fármacos , Proteínas de Transporte de Membrana/genética , Fenoles/farmacología , Profármacos/farmacología , Animales , Proteínas de Transporte de Membrana/metabolismo , Ratones , Ratones Noqueados , Transportadores de Ácidos Monocarboxílicos , Simportadores , Tiroxina/sangre , Triyodotironina/sangre , Proteína Desacopladora 2/genética , Proteína Desacopladora 2/metabolismo
13.
Neuroscience ; 372: 255-265, 2018 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-29337237

RESUMEN

Schwann cells (SCs) play a key role in peripheral nerve regeneration. After damage, they respond acquiring a repair phenotype that allows them to proliferate, migrate and redirect axonal growth. Previous studies have shown that Uridine-5'-Triphosphate (UTP) and its purinergic receptors participate in several pathophysiological responses in the nervous system. Our group has previously described how UTP induces the migration of a Schwannoma cell line and promotes wound healing. These data suggest that UTP participates in the signaling involved in the regeneration process. In the present study we evaluated UTP effects in isolated rat SCs and cocultures of SCs and dorsal root ganglia neurons. UTP reduced cAMP-dependent Krox-20 induction in SCs. UTP also reduced the N-cadherin re-expression that occurs when SCs and axons make contact. In myelinating cocultures, a non-significant tendency to a lower expression of P0 and MAG proteins in presence of UTP was observed. We also demonstrated that UTP induced SC migration without affecting cell proliferation. Interestingly, UTP was found to block neuregulin-induced phosphorylation of the ErbB3 receptor, a pathway involved in the regeneration process. These results indicate that UTP could acts as a brake to the differentiation signals, promoting a more migratory state in the repair-SCs.


Asunto(s)
Fármacos del Sistema Nervioso Periférico/farmacología , Células de Schwann/efectos de los fármacos , Uridina Trifosfato/farmacología , Animales , Axones/metabolismo , Cadherinas/metabolismo , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Técnicas de Cocultivo , AMP Cíclico/metabolismo , Proteína 2 de la Respuesta de Crecimiento Precoz/metabolismo , Ganglios Espinales/metabolismo , Fosforilación/efectos de los fármacos , Ratas Sprague-Dawley , Receptor ErbB-3/metabolismo , Células de Schwann/metabolismo , Regulación hacia Arriba/efectos de los fármacos
14.
J Clin Endocrinol Metab ; 99(12): E2799-804, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25222753

RESUMEN

CONTEXT: Mutations in the MCT8 (SLC16A2) gene, encoding a specific thyroid hormone transporter, cause an X-linked disease with profound psychomotor retardation, neurological impairment, and abnormal serum thyroid hormone levels. The nature of the central nervous system damage is unknown. OBJECTIVE: The objective of the study was to define the neuropathology of the syndrome by analyzing brain tissue sections from MCT8-deficient subjects. DESIGN: We analyzed brain sections from a 30th gestational week male fetus and an 11-year-old boy and as controls, brain tissue from a 30th and 28th gestational week male and female fetuses, respectively, and a 10-year-old girl and a 12-year-old boy. METHODS: Staining with hematoxylin-eosin and immunostaining for myelin basic protein, 70-kDa neurofilament, parvalbumin, calbindin-D28k, and synaptophysin were performed. Thyroid hormone determinations and quantitative PCR for deiodinases were also performed. RESULTS: The MCT8-deficient fetus showed a delay in cortical and cerebellar development and myelination, loss of parvalbumin expression, abnormal calbindin-D28k content, impaired axonal maturation, and diminished biochemical differentiation of Purkinje cells. The 11-year-old boy showed altered cerebellar structure, deficient myelination, deficient synaptophysin and parvalbumin expression, and abnormal calbindin-D28k expression. The MCT8-deficient fetal cerebral cortex showed 50% reduction of thyroid hormones and increased type 2 deiodinase and decreased type 3 deiodinase mRNAs. CONCLUSIONS: The following conclusions were reached: 1) brain damage in MCT8 deficiency is diffuse, without evidence of focal lesions, and present from fetal stages despite apparent normality at birth; 2) deficient hypomyelination persists up to 11 years of age; and 3) the findings are compatible with the deficient action of thyroid hormones in the developing brain caused by impaired transport to the target neural cells.


Asunto(s)
Daño Encefálico Crónico/congénito , Daño Encefálico Crónico/genética , Transportadores de Ácidos Monocarboxílicos/genética , Mutación/genética , Vaina de Mielina/genética , Vaina de Mielina/patología , Adulto , Encéfalo/patología , Daño Encefálico Crónico/patología , Diferenciación Celular/genética , Cerebelo/crecimiento & desarrollo , Cerebelo/patología , Corteza Cerebral/crecimiento & desarrollo , Corteza Cerebral/patología , Niño , Femenino , Humanos , Yoduro Peroxidasa/genética , Masculino , Neurogénesis/genética , Neuronas/patología , Embarazo , Simportadores , Hormonas Tiroideas/deficiencia
15.
PLoS One ; 9(6): e98998, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24905332

RESUMEN

In response to peripheral nerve injury, Schwann cells adopt a migratory phenotype and modify the extracellular matrix to make it permissive for cell migration and axonal re-growth. Uridine 5'-triphosphate (UTP) and other nucleotides are released during nerve injury and activate purinergic receptors expressed on the Schwann cell surface, but little is known about the involvement of purine signalling in wound healing. We studied the effect of UTP on Schwannoma cell migration and wound closure and the intracellular signaling pathways involved. We found that UTP treatment induced Schwannoma cell migration through activation of P2Y2 receptors and through the increase of extracellular matrix metalloproteinase-2 (MMP-2) activation and expression. Knockdown P2Y2 receptor or MMP-2 expression greatly reduced wound closure and MMP-2 activation induced by UTP. MMP-2 activation evoked by injury or UTP was also mediated by phosphorylation of all 3 major mitogen-activated protein kinases (MAPKs): JNK, ERK1/2, and p38. Inhibition of these MAPK pathways decreased both MMP-2 activation and cell migration. Interestingly, MAPK phosphorylation evoked by UTP exhibited a biphasic pattern, with an early transient phosphorylation 5 min after treatment, and a late and sustained phosphorylation that appeared at 6 h and lasted up to 24 h. Inhibition of MMP-2 activity selectively blocked the late, but not the transient, phase of MAPK activation. These results suggest that MMP-2 activation and late MAPK phosphorylation are part of a positive feedback mechanism to maintain the migratory phenotype for wound healing. In conclusion, our findings show that treatment with UTP stimulates in vitro Schwannoma cell migration and wound repair through a MMP-2-dependent mechanism via P2Y2 receptors and MAPK pathway activation.


Asunto(s)
Movimiento Celular/efectos de los fármacos , Metaloproteinasa 2 de la Matriz/metabolismo , Neurilemoma/patología , Uridina Trifosfato/farmacología , Línea Celular Tumoral , Activación Enzimática/efectos de los fármacos , Espacio Extracelular/efectos de los fármacos , Espacio Extracelular/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fosforilación/efectos de los fármacos , Receptores Purinérgicos P2Y/metabolismo , Cicatrización de Heridas/efectos de los fármacos
16.
PLoS One ; 8(10): e74621, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24098341

RESUMEN

Mutations of the monocarboxylate transporter 8 (MCT8) cause a severe X-linked intellectual deficit and neurological impairment. MCT8 is a specific thyroid hormone (T4 and T3) transporter and the patients also present unusual abnormalities in the serum profile of thyroid hormone concentrations due to altered secretion and metabolism of T4 and T3. Given the role of thyroid hormones in brain development, it is thought that the neurological impairment is due to restricted transport of thyroid hormones to the target neurons. In this work we have investigated cerebral metabolism in mice with Mct8 deficiency. Adult male mice were infused for 30 minutes with (1-(13)C) glucose and brain extracts prepared and analyzed by (13)C nuclear magnetic resonance spectroscopy. Genetic inactivation of Mct8 resulted in increased oxidative metabolism as reflected by increased glutamate C4 enrichment, and of glutamatergic and GABAergic neurotransmissions as observed by the increases in glutamine C4 and GABA C2 enrichments, respectively. These changes were distinct to those produced by hypothyroidism or hyperthyroidism. Similar increments in glutamate C4 enrichment and GABAergic neurotransmission were observed in the combined inactivation of Mct8 and D2, indicating that the increased neurotransmission and metabolic activity were not due to increased production of cerebral T3 by the D2-encoded type 2 deiodinase. In conclusion, Mct8 deficiency has important metabolic consequences in the brain that could not be correlated with deficiency or excess of thyroid hormone supply to the brain during adulthood.


Asunto(s)
Encéfalo/metabolismo , Proteínas de Transporte de Membrana/deficiencia , Proteínas de Transporte de Membrana/genética , Neurotransmisores/metabolismo , Animales , Activación Enzimática , Técnicas de Inactivación de Genes , Hipertiroidismo/metabolismo , Yoduro Peroxidasa/metabolismo , Masculino , Ratones , Transportadores de Ácidos Monocarboxílicos , Oxidación-Reducción , Simportadores , Hormonas Tiroideas/metabolismo , Yodotironina Deyodinasa Tipo II
17.
Int J Biochem Mol Biol ; 4(3): 140-9, 2013 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-24049669

RESUMEN

It is generally accepted that progression through the eukaryotic cell cycle is driven by cyclin-dependent kinases (CDKs), which are regulated by interaction with oscillatory expressed proteins called cyclins. CDKs may be separated into 2 categories: essential and non-essential. Understandably, more attention has been focused on essential CDKs because they are shown to control cell cycle progression to a greater degree. After clearly determining the basic and "core" mechanisms of essential CDKs, several questions arise. What role do non-essential CDKs play? Are these CDKs functionally redundant and do they serve as a mere backup? Or might they be responsible for some accessory tasks in cell cycle progression or control? In the present review we will try to answer these questions based on recent findings on the involvement of non-essential CDKs in cell cycle progression. We will analyse the most recent information with regard to these questions in the yeast Saccharomyces cerevisiae, a well-established eukaryotic model, and in its unique non-essential CDK involved in the cell cycle, Pho85. We will also briefly extend our discussion to higher eukaryotic systems.

18.
PLoS One ; 7(7): e40674, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22815787

RESUMEN

During nervous system development different cell-to-cell communication mechanisms operate in parallel guiding migrating neurons and growing axons to generate complex arrays of neural circuits. How such a system works in coordination is not well understood. Cross-regulatory interactions between different signalling pathways and redundancy between them can increase precision and fidelity of guidance systems. Immunoglobulin superfamily proteins of the NCAM and L1 families couple specific substrate recognition and cell adhesion with the activation of receptor tyrosine kinases. Thus it has been shown that L1CAM-mediated cell adhesion promotes the activation of the EGFR (erbB1) from Drosophila to humans. Here we explore the specificity of the molecular interaction between L1CAM and the erbB receptor family. We show that L1CAM binds physically erbB receptors in both heterologous systems and the mammalian developing brain. Different Ig-like domains located in the extracellular part of L1CAM can support this interaction. Interestingly, binding of L1CAM to erbB enhances its response to neuregulins. During development this may synergize with the activation of erbB receptors through L1CAM homophilic interactions, conferring diffusible neuregulins specificity for cells or axons that interact with the substrate through L1CAM.


Asunto(s)
Inmunoglobulinas/química , Molécula L1 de Adhesión de Célula Nerviosa/química , Molécula L1 de Adhesión de Célula Nerviosa/metabolismo , Neurregulinas/farmacología , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Adhesión Celular/efectos de los fármacos , Células HEK293 , Humanos , Células MCF-7 , Fosforilación/efectos de los fármacos , Unión Proteica/efectos de los fármacos , Estructura Terciaria de Proteína , Ratas , Secuencias Repetitivas de Aminoácido , Relación Estructura-Actividad
19.
Endocrinology ; 152(4): 1713-21, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21303950

RESUMEN

Mutations of the monocarboxylate transporter 8 gene (MCT8, SLC16A2) cause the Allan-Herndon-Dudley syndrome, an X-linked syndrome of severe intellectual deficit and neurological impairment. Mct8 transports thyroid hormones (T4 and T3), and the Allan-Herndon-Dudley syndrome is likely caused by lack of T3 transport to neurons during critical periods of fetal brain development. To evaluate the role of Mct8 in thyroid hormone action in the fetal brain we administered T4 or T3 to thyroidectomized pregnant dams treated with methyl-mercapto-imidazol to produce maternal and fetal hypothyroidism. Gene expression was then measured in the fetal cerebral cortex. T4 increased Camk4, Sema3c, and Slc7a3 expression, but T3 was without effect. To investigate the cause for the lack of T3 action we analyzed the expression of organic anion transport polypeptide (Oatp14, Slco1c1), a T4 transporter, and Mct8 (Slc16a2), a T4 and T3 transporter, by confocal microscopy. Both proteins were present in the brain capillaries forming the blood-brain barrier and in the epithelial cells of the choroid plexus forming the blood-cerebrospinal fluid barrier. It is concluded that T4 from the maternal compartment influences gene expression in the fetal cerebral cortex, possibly after transport via organic anion transporter polypeptide and/or Mct8, and conversion to T3 in the astrocytes. On the other hand, T3 does not reach the target neurons despite the presence of Mct8. The data indicate that T4, through local deiodination, provides most T3 in the fetal rat brain. The role of Mct8 as a T3 transporter in the fetal rat brain is therefore uncertain.


Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Triyodotironina/farmacología , Sistemas de Transporte de Aminoácidos Básicos/metabolismo , Animales , Encéfalo/embriología , Proteína Quinasa Tipo 4 Dependiente de Calcio Calmodulina/metabolismo , Femenino , Técnica del Anticuerpo Fluorescente , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Microscopía Confocal , Transportadores de Ácidos Monocarboxílicos/genética , Proteínas del Tejido Nervioso/metabolismo , Transportadores de Anión Orgánico/metabolismo , Proteínas de Transporte de Catión Orgánico , Ratas , Ratas Wistar , Tiroxina/farmacología
20.
Endocrinology ; 152(3): 1136-42, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21239431

RESUMEN

Thyroid hormone analogs with selective actions through specific thyroid hormone receptor (TR) subtypes are of great interest. They might offer the possibility of mimicking physiological actions of thyroid hormone with receptor subtype or tissue specificity with therapeutic aims. They are also pharmacological tools to dissect biochemical pathways mediated by specific receptor subtypes, in a complementary way to mouse genetic modifications. In this work, we studied the in vivo activity in developing rats of two thyroid hormone agonists, the TRß-selective GC-24 and the TRα-selective CO23. Our principal goal was to check whether these compounds were active in the rat brain. Analog activity was assessed by measuring the expression of thyroid hormone target genes in liver, heart, and brain, after administration to hypothyroid rats. GC-24 was very selective for TRß and lacked activity on the brain. On the other hand, CO23 was active in liver, heart, and brain on genes regulated by either TRα or TRß. This compound, previously shown to be TRα-selective in tadpoles, displayed no selectivity in the rat in vivo.


Asunto(s)
Acetatos/farmacología , Compuestos de Bencidrilo/farmacología , Hidantoínas/farmacología , Receptores alfa de Hormona Tiroidea/agonistas , Receptores beta de Hormona Tiroidea/agonistas , Animales , Encéfalo/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Corazón/efectos de los fármacos , Hipotiroidismo/tratamiento farmacológico , Hígado/efectos de los fármacos , Ratas , Ratas Wistar , Triyodotironina
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