RESUMEN

Irisin, a hormone-like adipo-myokine, has garnered considerable attention in recent years for its potential impact in metabolic diseases. Its physiological effects are similar to those of thyroid hormones, prompting numerous investigations into potential correlations and interactions between irisin and thyroid function through various in vitro and animal experiments. However, existing studies suggest that the relationship between irisin and thyroid diseases is highly complex and multifaceted. In this paper, we have summarized the research results on serum irisin and thyroid function, providing an overview of advancements and constraints in current research on irisin and thyroid hormones. The aim is to offer insights and directions for future clinical trials in this field.

Asunto(s)

Fibronectinas , Enfermedades de la Tiroides , Humanos , Fibronectinas/sangre , Fibronectinas/metabolismo , Enfermedades de la Tiroides/sangre , Enfermedades de la Tiroides/metabolismo , Animales , Hormonas Tiroideas/sangre , Hormonas Tiroideas/metabolismo

RESUMEN

Reactive astrocytes play critical roles in the occurrence of various neurological diseases such as multiple sclerosis. Activation of astrocytes is often accompanied by a glycolysis-dominant metabolic switch. However, the role and molecular mechanism of metabolic reprogramming in activation of astrocytes have not been clarified. Here, we found that PKM2, a rate-limiting enzyme of glycolysis, displayed nuclear translocation in astrocytes of EAE (experimental autoimmune encephalomyelitis) mice, an animal model of multiple sclerosis. Prevention of PKM2 nuclear import by DASA-58 significantly reduced the activation of mice primary astrocytes, which was observed by decreased proliferation, glycolysis and secretion of inflammatory cytokines. Most importantly, we identified the ubiquitination-mediated regulation of PKM2 nuclear import by ubiquitin ligase TRIM21. TRIM21 interacted with PKM2, promoted its nuclear translocation and stimulated its nuclear activity to phosphorylate STAT3, NF-κB and interact with c-myc. Further single-cell RNA sequencing and immunofluorescence staining demonstrated that TRIM21 expression was upregulated in astrocytes of EAE. TRIM21 overexpressing in mice primary astrocytes enhanced PKM2-dependent glycolysis and proliferation, which could be reversed by DASA-58. Moreover, intracerebroventricular injection of a lentiviral vector to knockdown TRIM21 in astrocytes or intraperitoneal injection of TEPP-46, which inhibit the nuclear translocation of PKM2, effectively decreased disease severity, CNS inflammation and demyelination in EAE. Collectively, our study provides novel insights into the pathological function of nuclear glycolytic enzyme PKM2 and ubiquitination-mediated regulatory mechanism that are involved in astrocyte activation. Targeting this axis may be a potential therapeutic strategy for the treatment of astrocyte-involved neurological disease.

Asunto(s)

Astrocitos , Encefalomielitis Autoinmune Experimental , Ribonucleoproteínas , Regulación hacia Arriba , Animales , Astrocitos/metabolismo , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/genética , Ratones , Ribonucleoproteínas/metabolismo , Ribonucleoproteínas/genética , Hormonas Tiroideas/metabolismo , Hormonas Tiroideas/genética , Proteínas de Unión a Hormona Tiroide , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ratones Endogámicos C57BL , Piruvato Quinasa/metabolismo , Piruvato Quinasa/genética , Transporte Activo de Núcleo Celular , Femenino , Glucólisis , Ubiquitinación , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Núcleo Celular/metabolismo

RESUMEN

The nuclear hormone family of receptors regulates gene expression. The androgen receptor (AR), upon ligand binding and homodimerization, shuttles from the cytosol into the nucleus to activate gene expression. Thyroid hormone receptors (TRs), retinoic acid receptors (RARs), and the vitamin D receptor (VDR) are present in the nucleus bound to chromatin as a heterodimer with the retinoid X receptors (RXRs) and repress gene expression. Ligand binding leads to transcription activation. The hormonal ligands for these receptors play crucial roles to ensure the proper conduct of very many tissues and exert effects on prostate cancer (PCa) cells. Androgens support PCa proliferation and androgen deprivation alone or with chemotherapy is the standard therapy for PCa. RARγ activation and 3,5,3'-triiodo-L-thyronine (T3) stimulation of TRß support the growth of PCa cells. Ligand stimulation of VDR drives growth arrest, differentiation, and apoptosis of PCa cells. Often these receptors are explored as separate avenues to find treatments for PCa and other cancers. However, there is accumulating evidence to support receptor interactions and crosstalk of regulatory events whereby a better understanding might lead to new combinatorial treatments.

Asunto(s)

Neoplasias de la Próstata , Receptores Androgénicos , Receptores de Calcitriol , Receptores de Hormona Tiroidea , Humanos , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Masculino , Receptores de Calcitriol/metabolismo , Receptores Androgénicos/metabolismo , Receptores de Hormona Tiroidea/metabolismo , Animales , Hormonas Tiroideas/metabolismo , Terapia Molecular Dirigida

RESUMEN

The hypometabolism induced by fasting has great potential in maintaining health and improving survival in extreme environments, among which thyroid hormone (TH) plays an important role in the adaptation and the formation of new energy metabolism homeostasis during long-term fasting. In the present review, we emphasize the potential of long-term fasting to improve physical health and emergency rescue in extreme environments, introduce the concept and pattern of fasting and its impact on the body's energy metabolism consumption. Prolonged fasting has more application potential in emergency rescue in special environments. The changes of THs caused by fasting, including serum biochemical characteristics, responsiveness of the peripheral and central hypothalamus-pituitary-thyroid (HPT) axis, and differential changes of TH metabolism, are emphasized in particular. It was proposed that the variability between brain and liver tissues in THs uptake, deiodination activation and inactivation is the key regulatory mechanism for the cause of peripheral THs decline and central homeostasis. While hypothalamic tanycytes play a pivotal role in the fine regulation of the HPT negative feedback regulation during long-term fasting. The study progress of tanycytes on thyrotropin-releasing hormone (TRH) release and deiodination is described in detail. In conclusion, the combination of the decrease of TH metabolism in peripheral tissues and stability in the central HPT axis maintains the basal physiological requirement and new energy metabolism homeostasis to adapt to long-term food scarcity. The molecular mechanisms of this localized and differential regulation will be a key research direction for developing measures for hypometabolic applications in extreme environment.

Asunto(s)

Metabolismo Energético , Ayuno , Hormonas Tiroideas , Humanos , Ayuno/metabolismo , Ayuno/fisiología , Hormonas Tiroideas/metabolismo , Animales , Metabolismo Energético/fisiología , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/fisiología , Glándula Tiroides/metabolismo , Glándula Tiroides/fisiología , Homeostasis

RESUMEN

BACKGROUND: Mitochondria are known to be involved in mediating the calorigenic effects of thyroid hormones. With an abundance of these hormones, alterations in energy metabolism and cellular respiration take place, leading to the development of cardiac hypertrophy. Vitamin D has recently gained attention due to its involvement in the regulation of mitochondrial function, demonstrating promising potential in preserving the integrity and functionality of the mitochondrial network. The present study aimed to investigate the therapeutic potential of Vitamin D on cardiac hypertrophy induced by hyperthyroidism, with a focus on the contributions of mitophagy and apoptosis as possible underlying molecular mechanisms. METHODS AND RESULTS: The rats were divided into three groups: control; hyperthyroid; hyperthyroid + Vitamin D. Hyperthyroidism was induced by Levothyroxine administration for four weeks. Serum thyroid hormones levels, myocardial damage markers, cardiac hypertrophy indices, and histological examination were assessed. The assessment of Malondialdehyde (MDA) levels and the expression of the related genes were conducted using heart tissue samples. Vitamin D pretreatment exhibited a significant improvement in the hyperthyroidism-induced decline in markers indicative of myocardial damage, oxidative stress, and indices of cardiac hypertrophy. Vitamin D pretreatment also improved the downregulation observed in myocardial expression levels of genes involved in the regulation of mitophagy and apoptosis, including PTEN putative kinase 1 (PINK1), Mitofusin-2 (MFN2), Dynamin-related Protein 1 (DRP1), and B cell lymphoma-2 (Bcl-2), induced by hyperthyroidism. CONCLUSIONS: These results suggest that supplementation with Vitamin D could be advantageous in preventing the progression of cardiac hypertrophy and myocardial damage.

Asunto(s)

Apoptosis , Cardiomegalia , Cardiotónicos , Modelos Animales de Enfermedad , Hipertiroidismo , Mitofagia , Tiroxina , Vitamina D , Animales , Hipertiroidismo/complicaciones , Hipertiroidismo/metabolismo , Hipertiroidismo/tratamiento farmacológico , Mitofagia/efectos de los fármacos , Apoptosis/efectos de los fármacos , Ratas , Tiroxina/farmacología , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/metabolismo , Vitamina D/farmacología , Masculino , Cardiotónicos/farmacología , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Miocardio/metabolismo , Miocardio/patología , Proteínas Quinasas/metabolismo , Proteínas Quinasas/genética , Malondialdehído/metabolismo , Hormonas Tiroideas/metabolismo

RESUMEN

Sexual dimorphism in plumage is widespread among avian species. In chickens, adult females exhibit countershading, characterized by dull-colored round feathers lacking fringe on the saddle, while adult males display vibrant plumage with deeply fringed bright feathers. This dimorphism is estrogen-dependent, and administering estrogen to males transforms their showy plumage into cryptic female-like plumage. Extensive studies have shown that estrogen's role in female plumage formation requires thyroid hormone; however, the precise mechanisms of their interaction remain unclear. In this study, we investigated the roles of estrogen and thyroid hormone in creating sexual dimorphism in the structure and coloration of saddle feathers by administering each hormone to adult males and observing the resulting changes in regenerated feathers induced by plucking. RT-PCR analysis revealed that the expression of type 3 deiodinase (DIO3), responsible for thyroid hormone inactivation, correlates with fringing. Estrogen suppressed DIO3 and agouti signaling protein (ASIP) expression while stimulating BlSK1, a marker of barbule cells, resulting in female-like feathers with mottled patterns and lacking fringes. Administration of thyroxine (T4) stimulated BlSK1 and proopiomelanocortin (POMC) expression, with no effect on ASIP, leading to the formation of solid black feathers lacking fringes. Triiodothyronine (T3) significantly increased POMC expression in pulp cells in culture. Taken together, these findings suggest that estrogen promotes the formation of solid vanes by suppressing DIO3 expression, while also inducing the formation of mottled patterns through inhibition of ASIP expression and indirect stimulation of melanocortin expression via changes in local T3 concentration. This is the first report describing molecular mechanism underlying hormonal crosstalk in creating sexual dimorphism in feathers.

Asunto(s)

Pollos , Plumas , Caracteres Sexuales , Animales , Plumas/metabolismo , Pollos/metabolismo , Masculino , Femenino , Hormonas Tiroideas/metabolismo , Estrógenos/metabolismo , Estrógenos/farmacología

RESUMEN

Gestating mice were exposed to three chemicals, tetrabromo-bisphenol A (TBBPA; 2 mg/kg/day), amitrole (25 and 50 mg/kg/day) and pyraclostrobin (0.4 and 2 mg/kg/day) to assess their capacity to act as thyroid hormone disruptors and compromise neurodevelopment. Propyl-thio-uracyl, a known pharmacological inhibitor of thyroid gland secretion, was used at both high and low dose as a reference thyroid hormone system disruptor (1 ppm, 1500 ppm). A combination of plasma metabolomics and striatum transcriptomics revealed the induced change in pups at the postnatal stages. Although the underlying mechanism is unlikely to involve thyroid hormone disruption, these chemicals had a detectable effect on pups' neurodevelopment.

Asunto(s)

Disruptores Endocrinos , Metabolómica , Efectos Tardíos de la Exposición Prenatal , Hormonas Tiroideas , Transcriptoma , Animales , Femenino , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Hormonas Tiroideas/sangre , Hormonas Tiroideas/metabolismo , Ratones , Disruptores Endocrinos/toxicidad , Transcriptoma/efectos de los fármacos , Masculino , Fenoles/toxicidad , Bifenilos Polibrominados

RESUMEN

Glycolysis occurs in all living organisms as a form of energy supply. Pyruvate kinase M2 (PKM2) is one of the rate­limiting enzymes in the glycolytic process. PKM2 is considered to serve an important role in several terminal diseases, including sepsis. However, to the best of our knowledge, the specific mechanistic role of PKM2 in sepsis remains to be systematically summarised. Therefore, the present review aims to summarise the roles of PKM2 in sepsis progression. In addition, potential treatment strategies for patients with sepsis are discussed. The present review hopes to lay the groundwork for studying the role of PKM2 and developing therapeutic strategies against metabolic disorders that occur during sepsis.

Asunto(s)

Piruvato Quinasa , Sepsis , Humanos , Sepsis/metabolismo , Piruvato Quinasa/metabolismo , Glucólisis , Animales , Proteínas de Unión a Hormona Tiroide , Hormonas Tiroideas/metabolismo

RESUMEN

It is well established that pyruvate kinase M2 (PKM2) activity contributes to metabolic reprogramming in various cancers, including colorectal cancer (CRC). Estrogen or 17ß-estradiol (E2) signaling is also known to modulate glycolysis markers in cancer cells. However, whether the inhibition of PKM2 combined with E2 treatment could adversely affect glucose metabolism in CRC cells remains to be investigated. First, we confirmed the metabolic plasticity of CRC cells under varying environmental conditions. Next, we identified glycolysis markers that were upregulated in CRC patients and assessed in vitro mRNA levels following E2 treatment. We found that PKM2 expression, which is highly upregulated in CRC clinical samples, is not altered by E2 treatment in CRC cells. In this study, glucose uptake, generation of reactive oxygen species (ROS), lactate production, cell viability, and apoptosis were evaluated in CRC cells following E2 treatment, PKM2 silencing, or a combination of both. Compared to individual treatments, combination therapy resulted in a significant reduction in cell viability and enhanced apoptosis. Glucose uptake and ROS production were markedly reduced in PKM2-silenced E2-treated cells. The data presented here suggest that E2 signaling combined with PKM2 inhibition cumulatively targets glucose metabolism in a manner that negatively impacts CRC cell growth. These findings hold promise for novel therapeutic strategies targeting altered metabolic pathways in CRC.

Asunto(s)

Neoplasias Colorrectales , Humanos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Hormonas Tiroideas/metabolismo , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismo , Estrógenos/farmacología , Proteínas de Unión a Hormona Tiroide , Estradiol/farmacología , Apoptosis/efectos de los fármacos , Glucosa/metabolismo , Proteínas Portadoras/metabolismo , Piruvato Quinasa/metabolismo , Piruvato Quinasa/antagonistas & inhibidores , Piruvato Quinasa/genética , Glucólisis/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Femenino

RESUMEN

In this issue of Cell Metabolism, Li et al. report that the highly expressed aldehyde dehydrogenase 1 family member A3 interacts with pyruvate kinase M2 (PKM2) in glioblastoma cells. Consequently, PKM2 tetramerization and activation promote lactate production, leading to the lactylation and nuclear translocation of XRCC1 for DNA damage repair and therapeutic resistance.

Asunto(s)

Daño del ADN , Reparación del ADN , Humanos , Glioblastoma/metabolismo , Glioblastoma/patología , Glioblastoma/genética , Efecto Warburg en Oncología , Proteínas de Unión al ADN/metabolismo , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/metabolismo , Proteínas de Unión a Hormona Tiroide , Hormonas Tiroideas/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas Portadoras/metabolismo , Aldehído Deshidrogenasa/metabolismo , Aldehído Deshidrogenasa/genética

RESUMEN

Patients with high ALDH1A3-expressing glioblastoma (ALDH1A3hi GBM) show limited benefit from postoperative chemoradiotherapy. Understanding the mechanisms underlying such resistance in these patients is crucial for the development of new treatments. Here, we show that the interaction between ALDH1A3 and PKM2 enhances the latter's tetramerization and promotes lactate accumulation in glioblastoma stem cells (GSCs). By scanning the lactylated proteome in lactate-accumulating GSCs, we show that XRCC1 undergoes lactylation at lysine 247 (K247). Lactylated XRCC1 shows a stronger affinity for importin α, allowing for greater nuclear transposition of XRCC1 and enhanced DNA repair. Through high-throughput screening of a small-molecule library, we show that D34-919 potently disrupts the ALDH1A3-PKM2 interaction, preventing the ALDH1A3-mediated enhancement of PKM2 tetramerization. In vitro and in vivo treatment with D34-919 enhanced chemoradiotherapy-induced apoptosis of GBM cells. Together, our findings show that ALDH1A3-mediated PKM2 tetramerization is a potential therapeutic target to improve the response to chemoradiotherapy in ALDH1A3hi GBM.

Asunto(s)

Glioblastoma , Proteínas de Unión a Hormona Tiroide , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X , Glioblastoma/metabolismo , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Humanos , Animales , Línea Celular Tumoral , Ratones , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/metabolismo , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Ratones Desnudos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Proteínas de la Membrana/metabolismo , Proteínas Portadoras/metabolismo , Hormonas Tiroideas/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Aldehído Oxidorreductasas , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH

RESUMEN

Medium-chain chlorinated paraffins (MCCPs, C14-C17) are frequently detected in diverse environmental media. It has been proposed to be listed in Annex A of the Convention on Persistent Organic Pollutants in 2023. Although MCCPs are a crucial health concern, their toxicity remains unclear. This study investigated the toxic effects of MCCPs (0.1-50 mg/kg body weight/day) on the thyroid gland of female Sprague-Dawley rats and characterized the potential toxic pathways via transcriptomics and metabolomics approaches. MCCPs exposure caused histopathological changes to the endoplasmic reticula and mitochondria in thyroid follicular cells at a dose of 50 mg/kg bw/d and increased serum thyrotropin-releasing hormone, thyroid-stimulating hormones, and thyroxine when exposed to a higher dose of MCCPs. Transcriptomic analysis indicated the excessive expression of key genes related to thyroid hormone synthesis induced by MCCPs. Integrating the dual-omics analysis revealed mitochondrial dysfunction of the thyroid by mediating fatty acid oxidation, Kreb's cycle, and oxidative phosphorylation. Significant metabolic toxicity on the thyroid might be linked to the characteristics of the chlorine content of MCCPs. This study revealed the toxicity of MCCPs to the thyroid gland via triggering thyroid hormone synthesis and interfering with mitochondrial function, which can provide new insights into the modes of action and mechanism-based risk assessment of MCCPs.

Asunto(s)

Mitocondrias , Parafina , Ratas Sprague-Dawley , Glándula Tiroides , Hormonas Tiroideas , Ratas , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/metabolismo , Hormonas Tiroideas/metabolismo , Animales , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Femenino

RESUMEN

Hypothyroidism is commonly detected in patients with medulloblastoma (MB). However, whether thyroid hormone (TH) contributes to MB pathogenicity remains undetermined. Here, we find that TH plays a critical role in promoting tumor cell differentiation. Reduction in TH levels frees the TH receptor, TRα1, to bind to EZH2 and repress expression of NeuroD1, a transcription factor that drives tumor cell differentiation. Increased TH reverses EZH2-mediated repression of NeuroD1 by abrogating the binding of EZH2 and TRα1, thereby stimulating tumor cell differentiation and reducing MB growth. Importantly, TH-induced differentiation of tumor cells is not restricted by the molecular subgroup of MB, suggesting that TH can be used to broadly treat MB subgroups. These findings establish an unprecedented association between TH signaling and MB pathogenicity, providing solid evidence for TH as a promising modality for MB treatment.

Asunto(s)

Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Diferenciación Celular , Proteína Potenciadora del Homólogo Zeste 2 , Meduloblastoma , Hormonas Tiroideas , Meduloblastoma/patología , Meduloblastoma/metabolismo , Meduloblastoma/genética , Humanos , Diferenciación Celular/efectos de los fármacos , Animales , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Ratones , Hormonas Tiroideas/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Neoplasias Cerebelosas/patología , Neoplasias Cerebelosas/metabolismo , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/tratamiento farmacológico , Línea Celular Tumoral , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Receptores alfa de Hormona Tiroidea/metabolismo , Receptores alfa de Hormona Tiroidea/genética , Transducción de Señal/efectos de los fármacos

RESUMEN

Because of its ubiquitous occurrence in the environment, decabromodiphenyl ethane (DBDPE), a novel brominated flame retardant, has been widely concerned. However, its transgenerational thyroid disrupting potential and intricate mechanism are barely explored. Therefore, zebrafish embryos were exposed to environmentally relevant concentrations of DBDPE (0, 0.1, 1 and 10 nM) until sexual maturity. The results indicated that life-time exposure to DBDPE caused anxiety-like behavior in unexposed offspring. Furthermore, the changing of thyroid hormones as well as transcriptional and DNA methylation level in the promoter region of related genes were evaluated. The thyroid disruptions observed in F1 larvae were primarily attributed to excessive transfer of thyroid hormone from F0 adults to F1 eggs. Conversely, the disruptions in F2 larvae were likely due to inherited epigenetic changes, specifically hypomethylation of crh and hypermethylation of ugt1ab, passed down from the F1 generation. Additionally, our results revealed sex-specific responses of the hypothalamic-pituitary-thyroid (HPT) axis in adult zebrafish. Furthermore, thyroid disruptions observed in unexposed offspring were more likely inherited from their mothers. The current results prompted our in-depth understanding of the multi- and transgenerational toxicity by DBDPE, and also highlighted the need to consider their adverse effects on persistent and inheritable epigenetic changes in future research on emerging pollutants.

Asunto(s)

Bromobencenos , Epigénesis Genética , Retardadores de Llama , Glándula Tiroides , Pez Cebra , Animales , Glándula Tiroides/efectos de los fármacos , Retardadores de Llama/toxicidad , Bromobencenos/toxicidad , Disruptores Endocrinos/toxicidad , Metilación de ADN/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Hormonas Tiroideas/metabolismo , Sistema Endocrino/efectos de los fármacos , Femenino , Masculino

RESUMEN

Most teleost fishes exhibit a biphasic life history with a larval oceanic phase that is transformed into morphologically and physiologically different demersal, benthic, or pelagic juveniles. This process of transformation is characterized by a myriad of hormone-induced changes, during the often abrupt transition between larval and juvenile phases called metamorphosis. Thyroid hormones (TH) are known to be instrumental in triggering and coordinating this transformation but other hormonal systems such as corticoids, might be also involved as it is the case in amphibians. In order to investigate the potential involvement of these two hormonal pathways in marine fish post-embryonic development, we used the Malabar grouper (Epinephelus malabaricus) as a model system. We assembled a chromosome-scale genome sequence and conducted a transcriptomic analysis of nine larval developmental stages. We studied the expression patterns of genes involved in TH and corticoid pathways, as well as four biological processes known to be regulated by TH in other teleost species: ossification, pigmentation, visual perception, and metabolism. Surprisingly, we observed an activation of many of the same pathways involved in metamorphosis also at an early stage of the larval development, suggesting an additional implication of these pathways in the formation of early larval features. Overall, our data brings new evidence to the controversial interplay between corticoids and thyroid hormones during metamorphosis as well as, surprisingly, during the early larval development. Further experiments will be needed to investigate the precise role of both pathways during these two distinct periods and whether an early activation of both corticoid and TH pathways occurs in other teleost species.

Asunto(s)

Larva , Metamorfosis Biológica , Animales , Metamorfosis Biológica/genética , Larva/crecimiento & desarrollo , Larva/genética , Larva/metabolismo , Regulación del Desarrollo de la Expresión Génica , Transcriptoma , Perfilación de la Expresión Génica , Lubina/genética , Lubina/crecimiento & desarrollo , Lubina/metabolismo , Hormonas Tiroideas/metabolismo

RESUMEN

Pyruvate kinase M2 (PKM2) is a key metabolic enzyme. Yet, its role in cerebral ischemia injury remains unclear. In this study we demonstrated that PKM2 expression was increased in the microglia after mouse cerebral ischemia-reperfusion (I/R) injury. We found that microglial polarization-mediated pro-inflammatory effect was mediated by PKM2 after cerebral I/R. Mechanistically, our results revealed that nuclear PKM2 mediated ischemia-induced microglial polarization through association with acetyl-H3K9. Hif-1α mediated the effect of nuclear PKM2/histone H3 on microglial polarization. PKM2-dependent Histone H3/Hif-1α modifications contributed the expression of CCL2 and induced up-regulation of microglial polarization in peri-infarct, resulting in neuroinflammation. Inhibiting nuclear translocation of microglial PKM2 reduced ischemia-induced pro-inflammation and promoted neuronal survival. Together, this study identifies nucleus PKM2 as a crucial mediator for regulating ischemia-induced neuroinflammation, suggesting PKM2 as a potential therapeutic target in ischemic stroke.

Asunto(s)

Ratones Endogámicos C57BL , Microglía , Enfermedades Neuroinflamatorias , Piruvato Quinasa , Daño por Reperfusión , Animales , Microglía/metabolismo , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Masculino , Piruvato Quinasa/metabolismo , Ratones , Enfermedades Neuroinflamatorias/patología , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/metabolismo , Isquemia Encefálica/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Regulación hacia Abajo , Núcleo Celular/metabolismo , Histonas/metabolismo , Neuroprotección , Quimiocina CCL2/metabolismo , Quimiocina CCL2/genética , Células Cultivadas , Modelos Animales de Enfermedad , Neuronas/metabolismo , Neuronas/patología , Hormonas Tiroideas/metabolismo

RESUMEN

Allan-Herndon-Dudley syndrome (AHDS) is a rare X-linked disorder that causes severe neurological damage, for which there is no effective treatment. AHDS is due to inactivating mutations in the thyroid hormone transporter MCT8 that impair the entry of thyroid hormones into the brain, resulting in cerebral hypothyroidism. However, the pathophysiology of AHDS is still not fully understood and this is essential to develop therapeutic strategies. Based on evidence suggesting that thyroid hormone deficit leads to alterations in astroglial cells, including gliosis, in this work, we have evaluated astroglial impairments in MCT8 deficiency by means of magnetic resonance imaging, histological, ultrastructural, and immunohistochemical techniques, and by mining available RNA sequencing outputs. Apparent diffusion coefficient (ADC) imaging values obtained from magnetic resonance imaging showed changes indicative of alterations in brain cytoarchitecture in MCT8-deficient patients (n = 11) compared to control subjects (n = 11). Astroglial alterations were confirmed by immunohistochemistry against astroglial markers in autopsy brain samples of an 11-year-old and a 30th gestational week MCT8-deficient subjects in comparison to brain samples from control subjects at similar ages. These findings were validated and further explored in a mouse model of AHDS. Our findings confirm changes in all the astroglial populations of the cerebral cortex in MCT8 deficiency that impact astrocytic metabolic and mitochondrial cellular respiration functions. These impairments arise early in brain development and persist at adult stages, revealing an abnormal distribution, density, morphology of cortical astrocytes, along with altered transcriptome, compatible with an astrogliosis-like phenotype at adult stages. We conclude that astrocytes are potential novel therapeutic targets in AHDS, and we propose ADC imaging as a tool to monitor the progression of neurological impairments and potential effects of treatments in MCT8 deficiency.

Asunto(s)

Astrocitos , Encéfalo , Transportadores de Ácidos Monocarboxílicos , Hipotonía Muscular , Simportadores , Hormonas Tiroideas , Astrocitos/metabolismo , Astrocitos/patología , Animales , Ratones , Humanos , Transportadores de Ácidos Monocarboxílicos/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Masculino , Encéfalo/metabolismo , Encéfalo/patología , Hormonas Tiroideas/metabolismo , Niño , Simportadores/metabolismo , Simportadores/genética , Hipotonía Muscular/metabolismo , Hipotonía Muscular/genética , Hipotonía Muscular/patología , Discapacidad Intelectual Ligada al Cromosoma X/genética , Discapacidad Intelectual Ligada al Cromosoma X/metabolismo , Discapacidad Intelectual Ligada al Cromosoma X/patología , Femenino , Adulto , Imagen por Resonancia Magnética/métodos , Atrofia Muscular

RESUMEN

Purpose: The main objective of this study was to explore the mechanism of effective component compatibility of Bufei Yishen formula III (ECC-BYF III) in inhibiting mitochondrial oxidative stress in a rat model of chronic obstructive pulmonary disease (COPD). Methods: A549 cells exposed to cigarette smoke extract (CSE) were used to establish a model of mitochondrial oxidative damage. The cells were treated with the plasmid encoding Pkm2 and the enzymes and proteins involved in oxidative stress and mitochondrial function were measured. A rat model of COPD was established using CS and bacteria. Two different treatments were established, ECC-BYF III (5.5 mg/kg/d) and N-acetylcysteine (54 mg/kg/day). Animals were tested for pulmonary function (Vt, PEF, FVC, FEV0.1s and Cdyn) after eight weeks of therapy and were sacrificed. Pulmonary H&E staining was performed, and the total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), total antioxidant capacity (T-AOC), and malondialdehyde (MDA) content were measured. The mitochondrial function was also examined. Furthermore, the Pkm2/Nrf2 signaling pathway was evaluated. Results: Overexpression of Pkm2 dramatically ameliorated the CS-induced mitochondrial oxidative damage. Further studies indicated that ECC-BYF III significantly improved mitochondrial function and inhibited oxidative stress in the lung tissues of COPD rats. Moreover, it can upregulate mitochondrial respiratory chain enzyme activity. ECC-BYF III also decreased the MDA content and increased T-SOD, GSH-Px, and T-AOC expression to facilitate oxidative homeostasis. Finally, our results indicated that the Pkm2/Nrf2 pathway is regulated by ECC-BYF III in A549 cells and lung tissue. Conclusion: These results indicate that ECC-BYF III exerts a strong effective therapeutic effect against cigarette smoke combined with bacteria-induced COPD in rats by activating the Pkm2/Nrf2 signaling pathway and restoring mitochondrial oxidative stress. Although more in vivo animal model research is needed to confirm these findings, this study contributes new data to support the conventional usage of ECC-BYF III.

Asunto(s)

Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos , Pulmón , Mitocondrias , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Enfermedad Pulmonar Obstructiva Crónica , Transducción de Señal , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Humanos , Estrés Oxidativo/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/fisiopatología , Pulmón/enzimología , Medicamentos Herbarios Chinos/farmacología , Células A549 , Masculino , Proteínas de Unión a Hormona Tiroide , Piruvato Quinasa/metabolismo , Antioxidantes/farmacología , Ratas Sprague-Dawley , Proteínas Portadoras/metabolismo , Hormonas Tiroideas/metabolismo , Humo/efectos adversos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética

RESUMEN

BACKGROUND: Variation in thyroid function parameters within the normal range has been observationally associated with adverse health outcomes. Whether those associations reflect causal effects is largely unknown. METHODS: We systematically tested associations between genetic differences in thyrotropin (TSH) and free thyroxine (FT4) within the normal range and more than 1100 diseases and more than 6000 molecular traits (metabolites and proteins) in three large population-based cohorts. This was performed by combining individual and summary level genetic data and using polygenic scores and Mendelian randomization (MR) methods. We performed a phenome-wide MR study in the OpenGWAS database covering thousands of complex phenotypes and diseases. FINDINGS: Genetically predicted TSH or FT4 levels within the normal range were predominately associated with thyroid-related outcomes, like goitre. The few extra-thyroidal outcomes that were found to be associated with genetic liability towards high but normal TSH levels included atrial fibrillation (odds ratio = 0.92, p-value = 2.13 × 10-3), thyroid cancer (odds ratio = 0.57, p-value = 2.97 × 10-4), and specific biomarkers, such as sex hormone binding globulin (ß = -0.046, p-value = 1.33 × 10-6) and total cholesterol (ß = 0.027, p-value = 5.80 × 10-3). INTERPRETATION: In contrast to previous studies that have described the association with thyroid hormone levels and disease outcomes, our genetic approach finds little evidence of an association between genetic differences in thyroid function within the normal range and non-thyroidal phenotypes. The association described in previous studies may be explained by reverse causation and confounding. FUNDING: This research was funded by the Swiss National Science Foundation (P1BEP3_200041). The Fenland study (DOI 10.22025/2017.10.101.00001) is funded by the Medical Research Council (MC_UU_12015/1, MC_PC_13046 and MC_UU_00006/1). The EPIC-Norfolk study (DOI 10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1, MC-UU_12015/1, MC_PC_13048 and MC_UU_00006/1).

Asunto(s)

Análisis de la Aleatorización Mendeliana , Hormonas Tiroideas , Humanos , Hormonas Tiroideas/sangre , Hormonas Tiroideas/metabolismo , Biomarcadores , Tirotropina/sangre , Fenotipo , Polimorfismo de Nucleótido Simple , Tiroxina/sangre , Predisposición Genética a la Enfermedad , Herencia Multifactorial , Estudio de Asociación del Genoma Completo , Pruebas de Función de la Tiroides , Enfermedades de la Tiroides/genética , Enfermedades de la Tiroides/diagnóstico , Enfermedades de la Tiroides/sangre

RESUMEN

Sirtuin 1 (SIRT1) is a histone deacetylase and plays diverse functions in various physiological events, from development to lifespan regulation. Here, in Parkinson's disease (PD) model mice, we demonstrated that SIRT1 ameliorates parkinsonism, while SIRT1 knockdown further aggravates PD phenotypes. Mechanistically, SIRT1 interacts with and deacetylates pyruvate kinase M2 (PKM2) at K135 and K206, thus leading to reduced PKM2 enzyme activity and lactate production, which eventually results in decreased glial activation in the brain. Administration of lactate in the brain recapitulates PD-like phenotypes. Furthermore, increased expression of PKM2 worsens PD symptoms, and, on the contrary, inhibition of PKM2 by shikonin or PKM2-IN-1 alleviates parkinsonism in mice. Collectively, our data indicate that excessive lactate in the brain might be involved in the progression of PD. By improving lactate homeostasis, SIRT1, together with PKM2, are likely drug targets for developing agents for the treatment of neurodegeneration in PD.

Asunto(s)

Encéfalo , Homeostasis , Ácido Láctico , Piruvato Quinasa , Sirtuina 1 , Sirtuina 1/metabolismo , Sirtuina 1/genética , Animales , Encéfalo/metabolismo , Encéfalo/patología , Piruvato Quinasa/metabolismo , Piruvato Quinasa/genética , Ratones , Ácido Láctico/metabolismo , Humanos , Acetilación/efectos de los fármacos , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/genética , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos C57BL , Proteínas de Unión a Hormona Tiroide , Hormonas Tiroideas/metabolismo , Naftoquinonas/farmacología