RESUMEN

Estrogen-related receptor gamma (ERRγ) is a member of the ERR orphan nuclear receptor family which possesses three subtypes, α, ß, and γ. ERRγ is reportedly predominantly expressed in metabolically active tissues and cells, which promotes positive and negative effects in different tissues. ERRγ overexpression in the liver, pancreas, and thyroid cells is related to liver cancer, oxidative stress, reactive oxygen species (ROS) regulation, and carcinoma. Reduced ERRγ expression in the brain, immune cells, tumor cells, and energy metabolism causes neurological dysfunction, gastric cancer, and obesity. ERRγ is a constitutive receptor; however, its transcriptional activity also depends on co-regulators, agonists, and antagonists, which, when after forming a complex, can play a role in targeting and treating diseases. Moreover, ERRγ has proven crucial in regulating cellular and metabolic activity. However, many functions mediated via ERRγ remain unknown and require further exploration. Hence, considering the importance of ERRγ, this review focuses on the critical findings and interactions between ERRγ and co-regulators, agonists, and antagonists alongside its relationship with downstream and upstream signaling pathways and diseases. This review highlights new findings and provides a path to understanding the current ideas and future studies on ERRγ-mediated cellular activity.

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Receptores de Estrógenos , Humanos , Receptores de Estrógenos/metabolismo , Animales

RESUMEN

OBJECTIVES: The serotonin (5-hydroxytryptamine, 5-HT) receptor 1A (5-HT1AR) is closely associated with serotonergic neurotransmission in the brain, being the most prevalent and widely distributed receptor of its kind. The purpose of this study is to investigate the regulation mechanism of 5-HT1AR by GSK4716. METHODS: To investigate the mechanism of GSK4716-mediated 5-HT1AR regulation, we used hippocampus-derived HT22 cells expressing 5-HT1AR. The expression level of 5-HT1AR and associated proteins, were detected by reporter gene assay and western blotting. RESULTS: GSK4716, an estrogen-related receptor gamma agonist increased 5-HT1AR expression by interacting with the GR, a repressor of 5-HT1AR transcription. Dexamethasone, a GR agonist, decreased the GSK4716-induced increase in 5-HT1AR, which was associated with an alteration in nuclear GR. Furthermore, GR antagonist RU486 reversed the effects induced by dexamethasone, including the elevation of nuclear GR levels and the reduction of 5-HT1AR transcription and expression. CONCLUSION: The results could provide insight into the potential applications of small molecules, such as GSK4716, in the regulation of 5-HT1AR expression, which plays a role in serotonergic neurotransmission.

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Hipocampo , Receptor de Serotonina 5-HT1A , Receptores de Glucocorticoides , Animales , Ratones , Línea Celular , Dexametasona/farmacología , Estrógenos/farmacología , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Mifepristona/farmacología , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT1A/metabolismo , Receptores de Glucocorticoides/efectos de los fármacos , Receptores de Glucocorticoides/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología

RESUMEN

Engineered cardiac tissue (ECT) using human induced pluripotent stem cell-derived cardiomyocytes is a promising tool for modeling heart disease. However, tissue immaturity makes robust disease modeling difficult. Here, we established a method for modeling hypertrophic cardiomyopathy (HCM) malignant (MYH7 R719Q) and nonmalignant (MYBPC3 G115∗) pathogenic sarcomere gene mutations by accelerating ECT maturation using an ERRγ agonist, T112, and mechanical stretching. ECTs treated with T112 under 10% elongation stimulation exhibited more organized and mature characteristics. Whereas matured ECTs with the MYH7 R719Q mutation showed broad HCM phenotypes, including hypertrophy, hypercontraction, diastolic dysfunction, myofibril misalignment, fibrotic change, and glycolytic activation, matured MYBPC3 G115∗ ECTs displayed limited phenotypes, which were primarily observed only under our new maturation protocol (i.e., hypertrophy). Altogether, ERRγ activation combined with mechanical stimulation enhanced ECT maturation, leading to a more accurate manifestation of HCM phenotypes, including non-cardiomyocyte activation, consistent with clinical observations.

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Cardiomiopatía Hipertrófica , Células Madre Pluripotentes Inducidas , Humanos , Ingeniería de Tejidos , Proteínas Portadoras/genética , Células Madre Pluripotentes Inducidas/patología , Cardiomiopatía Hipertrófica/patología , Fenotipo , Miocitos Cardíacos/fisiología , Mutación , Hipertrofia/patología

RESUMEN

BACKGROUND: Glycolysis under normoxic conditions, known as the Warburg effect, confers a selective advantage for the survival and proliferation of many tumors. In this study, we investigated the role of estrogen-related receptor gamma (ESRRG) in metabolic reprogramming in esophageal squamous cell carcinoma (ESCC). METHODS: Bioinformatics analysis indicated that ESRRG expression was decreased in ESCC tissue and associated with poor clinical outcomes. We also examined the effects of altered ESRRG expression on the proliferation and metabolic reprogramming of ESCC cells. We explored the impact of ESRRG on Pyruvate kinase M2 (PKM2) expression and malignant behavior in ESCC. RESULTS: Our study revealed the inhibitory effects of ESRRG on the growth, tumorigenesis, and glycolysis activity of ESCC cells, which were mediated by the downregulation of PKM2 expression. We further demonstrated that ESRRG directly interacts with the PKM2 promoter to inhibit its activity in ESCC. Notably, the ESRRG-specific agonist, DY131, inhibited ESCC cell proliferation and glycolysis activity by modulating genes in the glycolysis pathway. Moreover, we verified that DY131 exhibits enhanced activity as an immune checkpoint inhibitor, considering the significance of the ESRRG-PKM2 axis in the lactate regulation of ESCC cells. CONCLUSION: Our findings provide novel insights into the role of ESRRG-PKM2 signaling in regulating ESCC cell metabolism and immune checkpoint regulation. Additionally, we suggest that DY131 holds promise as a promising therapeutic agent for ESCC treatment.

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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Regulación hacia Abajo , Carcinogénesis , Ácido Láctico , Receptores de Estrógenos

RESUMEN

Background Peripheral arterial disease and critical limb ischemia are cardiovascular complications associated with vascular insufficiency, oxidative metabolic dysfunction, and myopathy in the limbs. Estrogen-related receptor gamma (ERRγ) has emerged as a dual regulator of paracrine angiogenesis and oxidative metabolism through transgenic mouse studies. Here our objective was to investigate whether postischemic intramuscular targeting of ERRγ via gene therapy promotes ischemic recovery in a preclinical model of peripheral arterial disease/critical limb ischemia. Methods and Results Adeno-associated virus 9 (AAV9) Esrrg gene delivery vector was developed and first tested via intramuscular injection in murine skeletal muscle. AAV9-Esrrg robustly increased ERRγ protein expression, induced angiogenic and oxidative genes, and boosted capillary density and succinate dehydrogenase oxidative metabolic activity in skeletal muscles of C57Bl/6J mice. Next, hindlimb ischemia was induced via unilateral femoral vessel ligation in mice, followed by intramuscular AAV9-Esrrg (or AAV9-green fluorescent protein) gene delivery 24 hours after injury. ERRγ overexpression increased ischemic neoangiogenesis and markers of endothelial activation, and significantly improved ischemic revascularization measured using laser Doppler flowmetry. Moreover, ERRγ overexpression restored succinate dehydrogenase oxidative metabolic capacity in ischemic muscle, which correlated with increased mitochondrial respiratory complex protein expression. Most importantly, myofiber size to number quantification revealed that AAV9-Esrrg restores myofibrillar size and mitigates ischemia-induced myopathy. Conclusions These results demonstrate that intramuscular AAV9-Esrrg delivery rescues ischemic pathology after hindlimb ischemia, underscoring that Esrrg gene therapy or pharmacological activation could be a promising strategy for the management of peripheral arterial disease/critical limb ischemia.

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Enfermedad Arterial Periférica , Succinato Deshidrogenasa , Ratones , Animales , Succinato Deshidrogenasa/genética , Succinato Deshidrogenasa/metabolismo , Isquemia Crónica que Amenaza las Extremidades , Neovascularización Fisiológica/genética , Músculo Esquelético/irrigación sanguínea , Terapia Genética , Ratones Transgénicos , Enfermedad Arterial Periférica/terapia , Isquemia/genética , Isquemia/terapia , Isquemia/patología , Estrógenos/metabolismo , Miembro Posterior/irrigación sanguínea , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad

RESUMEN

Previously, we reported that an inverse agonist of estrogen-related receptor gamma (ERRγ), GSK5182, enhances sodium iodide (Na+/I-) symporter (NIS) function through mitogen-activated protein (MAP) kinase signaling in anaplastic thyroid cancer cells. This finding helped us to further investigate the effects of GSK5182 on NIS function in papillary thyroid cancer (PTC) refractory to radioactive iodine (RAI) therapy. Herein, we report the effects of ERRγ on the regulation of NIS function in RAI-resistant PTC cells using GSK5182. RAI-refractory BCPAP cells were treated with GK5182 for 24 h at various concentrations, and radioiodine avidity was determined with or without potassium perchlorate (KClO4) as an NIS inhibitor. We explored the effects of GSK5182 on ERRγ, the mitogen-activated protein (MAP) kinase pathway, and iodide metabolism-related genes. We examined whether the MAP pathway affected GSK5182-mediated NIS function using U0126, a selective MEK inhibitor. A clonogenic assay was performed to evaluate the cytotoxic effects of I-131. GSK5182 induced an increase in radioiodine avidity in a dose-dependent manner, and the enhanced uptake was completely inhibited by KClO4 in BCPAP cells. We found that ERRγ was downregulated and phosphorylated extracellular signal-regulated kinase (ERK)1/2 was upregulated in BCPAP cells, with an increase in total and membranous NIS and iodide metabolism-related genes. MEK inhibitors reversed the increase in radioiodine avidity induced by GSK5182. Clonogenic examination revealed the lowest survival in cells treated with a combination of GSK5182 and I-131 compared to those treated with either GSK518 or I-131 alone. We demonstrate that an inverse agonist of ERRγ, GSK5182, enhances the function of NIS protein via the modulation of ERRγ and MAP kinase signaling, thereby leading to increased responsiveness to radioiodine in RAI-refractory papillary thyroid cancer cells.

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Simportadores , Neoplasias de la Tiroides , Humanos , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/radioterapia , Neoplasias de la Tiroides/metabolismo , Radioisótopos de Yodo/uso terapéutico , Cáncer Papilar Tiroideo/tratamiento farmacológico , Cáncer Papilar Tiroideo/radioterapia , Yoduros/metabolismo , Agonismo Inverso de Drogas , Mitógenos , Simportadores/genética , Simportadores/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Estrógenos

RESUMEN

BACKGRUOUND: Excessive proliferation and migration of vascular smooth muscle cells (VSMCs), which contributes to the development of occlusive vascular diseases, requires elevated mitochondrial oxidative phosphorylation to meet the increased requirements for energy and anabolic precursors. Therefore, therapeutic strategies based on blockade of mitochondrial oxidative phosphorylation are considered promising for treatment of occlusive vascular diseases. Here, we investigated whether DN200434, an orally available estrogen receptor-related gamma inverse agonist, inhibits proliferation and migration of VSMCs and neointima formation by suppressing mitochondrial oxidative phosphorylation. METHODS: VSMCs were isolated from the thoracic aortas of 4-week-old Sprague-Dawley rats. Oxidative phosphorylation and the cell cycle were analyzed in fetal bovine serum (FBS)- or platelet-derived growth factor (PDGF)-stimulated VSMCs using a Seahorse XF-24 analyzer and flow cytometry, respectively. A model of neointimal hyperplasia was generated by ligating the left common carotid artery in male C57BL/6J mice. RESULTS: DN200434 inhibited mitochondrial respiration and mammalian target of rapamycin complex 1 activity and consequently suppressed FBS- or PDGF-stimulated proliferation and migration of VSMCs and cell cycle progression. Furthermore, DN200434 reduced carotid artery ligation-induced neointima formation in mice. CONCLUSION: Our data suggest that DN200434 is a therapeutic option to prevent the progression of atherosclerosis.

Asunto(s)

Aterosclerosis , Neointima , Ratas , Ratones , Masculino , Animales , Neointima/prevención & control , Neointima/tratamiento farmacológico , Neointima/metabolismo , Músculo Liso Vascular/metabolismo , Ratones Endogámicos C57BL , Proliferación Celular , Ratas Sprague-Dawley , Células Cultivadas , Arteria Carótida Común/metabolismo , Arterias Carótidas/cirugía , Arterias Carótidas/metabolismo , Mamíferos

RESUMEN

Tick-borne encephalitis virus (TBEV), the most medically relevant tick-transmitted flavivirus in Eurasia, targets the host central nervous system and frequently causes severe encephalitis. The severity of TBEV-induced neuropathogenesis is highly cell-type specific and the exact mechanism responsible for such differences has not been fully described yet. Thus, we performed a comprehensive analysis of alterations in host poly-(A)/miRNA/lncRNA expression upon TBEV infection in vitro in human primary neurons (high cytopathic effect) and astrocytes (low cytopathic effect). Infection with severe but not mild TBEV strain resulted in a high neuronal death rate. In comparison, infection with either of TBEV strains in human astrocytes did not. Differential expression and splicing analyses with an in silico prediction of miRNA/mRNA/lncRNA/vd-sRNA networks found significant changes in inflammatory and immune response pathways, nervous system development and regulation of mitosis in TBEV Hypr-infected neurons. Candidate mechanisms responsible for the aforementioned phenomena include specific regulation of host mRNA levels via differentially expressed miRNAs/lncRNAs or vd-sRNAs mimicking endogenous miRNAs and virus-driven modulation of host pre-mRNA splicing. We suggest that these factors are responsible for the observed differences in the virulence manifestation of both TBEV strains in different cell lines. This work brings the first complex overview of alterations in the transcriptome of human astrocytes and neurons during the infection by two TBEV strains of different virulence. The resulting data could serve as a starting point for further studies dealing with the mechanism of TBEV-host interactions and the related processes of TBEV pathogenesis.

RESUMEN

Fetal growth restriction (FGR) describes a fetus which has not achieved its genetic growth potential; it is closely linked to placental dysfunction and uteroplacental hypoxia. Estrogen-related receptor gamma (ESRRG) is regulated by hypoxia and is highly expressed in the placenta. We hypothesized ESRRG is a regulator of hypoxia-mediated placental dysfunction in FGR pregnancies. Placentas were collected from women delivering appropriate for gestational age (AGA; n = 14) or FGR (n = 14) infants. Placental explants (n = 15) from uncomplicated pregnancies were cultured for up to 4 days in 21% or 1% O2, or with 200 µM cobalt chloride (CoCl2), or treated with the ESRRG agonists DY131 under different oxygen concentrations. RT-PCR, Western blotting, and immunochemistry were used to assess mRNA and protein levels of ESRRG and its localization in placental tissue from FGR or AGA pregnancies, and in cultured placental explants. ESRRG mRNA and protein expression were significantly reduced in FGR placentas, as was mRNA expression of the downstream targets of ESRRG, hydroxysteroid 11-beta dehydrogenase 2 (HSD11B2), and cytochrome P-450 (CYP19A1.1). Hypoxia-inducible factor 1-alpha protein localized to the nuclei of the cytotrophoblasts and stromal cells in the explants exposed to CoCl2 or 1% O2. Both hypoxia and CoCl2 treatment decreased ESRRG and its downstream genes' mRNA expression, but not ESRRG protein expression. DY131 increased the expression of ESRRG signaling pathways and prevented abnormal cell turnover induced by hypoxia. These data show that placental ESRRG is hypoxia-sensitive and altered ESRRG-mediated signaling may contribute to hypoxia-induced placental dysfunction in FGR. Furthermore, DY131 could be used as a novel therapeutic approach for the treatment of placental dysfunction.

Asunto(s)

Retardo del Crecimiento Fetal , Placenta , Cobalto/farmacología , Estrógenos/metabolismo , Estrógenos/farmacología , Femenino , Retardo del Crecimiento Fetal/genética , Retardo del Crecimiento Fetal/metabolismo , Humanos , Hipoxia/genética , Hipoxia/metabolismo , Placenta/metabolismo , Embarazo , ARN Mensajero/metabolismo

RESUMEN

Bisphenol A (BPA) exposure during pregnancy is associated with low fetal weight, particularly in male fetuses. The expression of estrogen-related receptor gamma (ESRRG), a receptor for BPA in the human placenta, is reduced in fetal growth restriction. This study sought to explore whether ESRRG signaling mediates BPA-induced placental dysfunction and determine whether changes in the ESRRG signaling pathway are sex-specific. Placental villous explants from 18 normal term pregnancies were cultured with a range of BPA concentrations (1 nM-1 µM). Baseline BPA concentrations in the placental tissue used for explant culture ranged from 0.04 to 5.1 nM (average 2.3 ±1.9 nM; n = 6). Expression of ESRRG signaling pathway constituents and cell turnover were quantified. BPA (1 µM) increased ESRRG mRNA expression after 24 h in both sexes. ESRRG mRNA and protein expression was increased in female placentas treated with 1 µM BPA for 24 h but was decreased in male placentas treated with 1 nM or 1 µM for 48 h. Levels of 17ß-hydroxysteroid dehydrogenase type 1 (HSD17B1) and placenta specific-1 (PLAC1), genes downstream of ESRRG, were also affected. HSD17B1 mRNA expression was increased in female placentas by 1 µM BPA; however, 1 nM BPA reduced HSD17B1 and PLAC1 expression in male placentas at 48 h. BPA treatment did not affect rates of proliferation, apoptosis, or syncytiotrophoblast differentiation in cultured villous explants. This study has demonstrated that BPA affects the ESRRG signaling pathway in a sex-specific manner in human placentas and a possible biological mechanism to explain the differential effects of BPA exposure on male and female fetuses observed in epidemiological studies.

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Placenta , Proteínas Gestacionales , Receptores de Estrógenos , Compuestos de Bencidrilo/toxicidad , Femenino , Humanos , Masculino , Fenoles , Placenta/metabolismo , Embarazo , Proteínas Gestacionales/metabolismo , ARN Mensajero , Receptores de Estrógenos/metabolismo , Transducción de Señal

RESUMEN

Midbrain dopaminergic (DAergic) neurotransmission plays a crucial role in regulating motor, cognitive, and emotional functions. The orphan nuclear receptor estrogen-related receptor gamma (ERRγ) is highly expressed in the adult brain and in the developing fetal brain. Our previous study showed the relevance of ERRγ in the regulation of the DAergic neuronal phenotype with the upregulation of dopamine synthesizing tyrosine hydroxylase (TH) and dopamine transporter (DAT) and the possibility that ERRγ could be a novel target for regulating DAergic neuronal differentiation. In this study, we examined whether ERRγ ligands could be small molecule regulators of DAergic phenotypes. The ERRγ agonist GSK4716 increased DAT and TH expression, and the ERRγ inverse agonist GSK5182 attenuated the retinoic acid-induced upregulation of DAT and TH in differentiated SH-SY5Y cells. We found that biphasic activation of the protein kinase A/cyclic AMP response element-binding (CREB) protein signaling pathway was involved in the GSK4716-induced increase in the DAergic phenotype in SH-SY5Y cells. CREB signaling activated as early as 3 h after GSK4716 treatment in an ERRγ-independent manner, but increased following ERRγ activation after 3 days. Protein kinase A inhibitor H-89 attenuated GSK4716-induced DAT and TH upregulation. In primary cultured DAergic neurons, GSK4716 increased neurite length and the number of DAT and TH-double-positive (DAT + TH+) neurons compared to that in control cells. These findings suggest that ERRγ ligands could serve as useful chemical tools for obtaining a better understanding of the regulation of DAergic phenotypes and might facilitate the development of small molecule therapeutics to treat DA-related neurological diseases.

Asunto(s)

Diferenciación Celular/efectos de los fármacos , Neuronas Dopaminérgicas/efectos de los fármacos , Estrógenos/farmacología , Transducción de Señal/efectos de los fármacos , Línea Celular Tumoral , Neuronas Dopaminérgicas/metabolismo , Homeostasis/efectos de los fármacos , Humanos , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacología , Activación Transcripcional/efectos de los fármacos , Tretinoina/metabolismo , Tirosina 3-Monooxigenasa/efectos de los fármacos , Tirosina 3-Monooxigenasa/metabolismo , Regulación hacia Arriba/efectos de los fármacos

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Type 2 diabetes mellitus (T2DM) steadily increases in prevalence since the 1950's, the period of widespread distribution of refrigerated pasteurized cow's milk. Whereas breastfeeding protects against the development of T2DM in later life, accumulating epidemiological evidence underlines the role of cow's milk consumption in T2DM. Recent studies in rodent models demonstrate that during the breastfeeding period pancreatic ß-cells are metabolically immature and preferentially proliferate by activation of mechanistic target of rapamycin complex 1 (mTORC1) and suppression of AMP-activated protein kinase (AMPK). Weaning determines a metabolic switch of ß-cells from a proliferating, immature phenotype with low insulin secretion to a differentiated mature phenotype with glucose-stimulated insulin secretion, less proliferation, reduced mTORC1- but increased AMPK activity. Translational evidence presented in this perspective implies for the first time that termination of milk miRNA transfer is the driver of this metabolic switch. miRNA-148a is a key inhibitor of AMPK and phosphatase and tensin homolog, crucial suppressors of mTORC1. ß-Cells of diabetic patients return to the postnatal phenotype with high mTORC1 and low AMPK activity, explained by continuous transfer of bovine milk miRNAs to the human milk consumer. Bovine milk miRNA-148a apparently promotes ß-cell de-differentiation to the immature mTORC1-high/AMPK-low phenotype with functional impairments in insulin secretion, increased mTORC1-driven endoplasmic reticulum stress, reduced autophagy and early ß-cell apoptosis. In contrast to pasteurized cow's milk, milk's miRNAs are inactivated by bacterial fermentation, boiling and ultra-heat treatment and are missing in current infant formula. Persistent milk miRNA signaling adds a new perspective to the pathogenesis of T2DM and explains the protective role of breastfeeding but the diabetogenic effect of continued milk miRNA signaling by persistent consumption of pasteurized cow's milk.

RESUMEN

Recent studies have established the importance of estrogen-related receptor γ (ERRγ) as a required participant for insulin secretion in pancreatic ß cells. Key downstream genes of ERRγ remain unclear in the pancreatic ß cell. To understand the molecular role of ERRγ and elucidate potential key candidate genes involved in pancreatic ß cells, the eukaryotic expression plasmid containing mouse ERRγ was constructed and transfected into NIT-1 pancreatic ß cells. Overexpression of ERRγ was confirmed by quantitative real-time reverse-transcription polymerase chain reaction and Western blot analyses. RNA-seq was conducted to get the gene expression profiling between the overexpression group cells and control cells. Differentially expressed genes (DEGs) were identified by edgR and subsequently analyzed by gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. We found that overexpression of ERRγ in pancreatic ß cells enables regulation of the expression of certain genes involved in cell apoptosis and mitochondrial function, such as TFPT, Bcl7c, Dap, Thoc6, Ube2d3, ATP5H, MPV17, and NDUFA6. GO analysis revealed that the DEGs were mainly enriched in apoptotic process, cytoplasm, and protein binding. KEGG pathway analysis demonstrated that downregulated DEGs were mainly enriched in protein processing in endoplasmic reticulum, estrogen signaling pathway, and metabolic pathways. This study helps to further understand and reposition the molecular mechanisms of ERRγ in ß cells.

Asunto(s)

Células Secretoras de Insulina/metabolismo , Receptores de Estrógenos/metabolismo , Animales , Perfilación de la Expresión Génica , Ontología de Genes , Humanos , Ratones , Receptores de Estrógenos/genética , Análisis de Secuencia de ARN

RESUMEN

BACKGROUND: Estrogen-related receptor gamma (ESRRG) has been identified as a tumor suppressor gene in several cancers. We aimed to evaluate ESRRG promoter methylation in laryngeal squamous cell carcinoma (LSCC) and its relative clinical value in LSCC. METHODS: Bisulfite pyrosequencing assays were performed on 91 pairs of tumor and paracancer tissues from LSCC patients in China. The diagnostic value and overall survival (OS) were analyzed descriptively by receiver operating characteristic (ROC) curves and the Kaplan-Meier methods, respectively. RESULTS: The ESRRG promoter was more frequently hypermethylated in tumor tissues than in adjacent tissues (P < 0.01). ESRRG promoter methylation was significantly increased in advanced T stage tumors (P < 0.01) and advanced clinical stage patients (P < 0.01). Moreover, the area under the ROC curve (AUC) value (0.81) indicated high discrimination accuracy. Furthermore, ESRRG hypermethylation was associated with poor OS, as confirmed by Kaplan-Meier survival curves (P < 0.01). CONCLUSION: Our study indicated that ESRRG promoter hypermethylation contributed to LSCC-related risks, primarily tumor progression and survival prognosis, in patients. ESRRG promoter methylation could, therefore, be a diagnostic and prognostic biomarker in LSCC.

Asunto(s)

Carcinoma de Células Escamosas/genética , Metilación de ADN , Neoplasias Laríngeas/genética , Regiones Promotoras Genéticas , Receptores de Estrógenos/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Humanos , Estimación de Kaplan-Meier , Neoplasias Laríngeas/mortalidad , Neoplasias Laríngeas/patología , Persona de Mediana Edad , Pronóstico , Curva ROC

RESUMEN

Brown adipose tissue (BAT) adaptively transfers energy from glucose and fat into heat by inducing a gene network that uncouples mitochondrial electron transport. However, the innate transcription factors that enable the rapid adaptive response of BAT are unclear. Here, we identify estrogen-related receptor gamma (ERRγ) as a critical factor for maintaining BAT identity. ERRγ is selectively expressed in BAT versus WAT, in which, in the absence of PGC1α, it drives a signature transcriptional network of thermogenic and oxidative genes in the basal (i.e., thermoneutral) state. Mice lacking ERRγ in adipose tissue (ERRγKO mice) display marked downregulation of BAT-selective genes that leads to a pronounced whitening of BAT. Consistent with the transcriptional changes, the thermogenic capacity of ERRγKO mice is severely blunted, such that they fail to survive an acute cold challenge. These findings reveal a role for ERRγ as a critical thermoneutral maintenance factor required to prime BAT for thermogenesis.

Asunto(s)

Tejido Adiposo Pardo/metabolismo , Metabolismo Energético/genética , Receptores de Estrógenos/metabolismo , Termogénesis/genética , Animales , Ratones

RESUMEN

GSK5182 (4) is currently one of the lead compounds for the development of estrogen-related receptor gamma (ERRγ) inverse agonists. Here, we report the design, synthesis, pharmacological and in vitro absorption, distribution, metabolism, excretion, toxicity (ADMET) properties of a series of compounds related to 4. Starting from 4, a series of analogs were structurally modified and their ERRγ inverse agonist activity was measured. A key pharmacophore feature of this novel class of ligands is the introduction of a heterocyclic group for A-ring substitution in the core scaffold. Among the tested compounds, several of them are potent ERRγ inverse agonists as determined by binding and functional assays. The most promising compound, 15g, had excellent binding selectivity over related subtypes (IC50 = 0.44, >10, >10, and 10 µM at the ERRγ, ERRα, ERRß, and ERα subtypes, respectively). Compound 15g also resulted in 95% transcriptional repression at a concentration of 10 µM, while still maintaining an acceptable in vitro ADMET profile. This novel class of ERRγ inverse agonists shows promise in the development of drugs targeting ERRγ-related diseases.

Asunto(s)

Estrógenos/farmacología , Receptores de Estrógenos/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Tamoxifeno/análogos & derivados , Animales , Sitios de Unión , Línea Celular , Sistema Enzimático del Citocromo P-450/química , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Estabilidad de Medicamentos , Canal de Potasio ERG1 , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Estrógenos/síntesis química , Canales de Potasio Éter-A-Go-Go/química , Canales de Potasio Éter-A-Go-Go/genética , Canales de Potasio Éter-A-Go-Go/metabolismo , Expresión Génica , Ensayos Analíticos de Alto Rendimiento , Humanos , Ligandos , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Unión Proteica , Ratas , Receptores de Estrógenos/química , Receptores de Estrógenos/genética , Bibliotecas de Moléculas Pequeñas/síntesis química , Relación Estructura-Actividad , Tamoxifeno/química , Tamoxifeno/farmacología , Termodinámica

RESUMEN

microRNAs (miRNAs or miRs) are small non-coding RNAs that are involved in post-transcriptional regulation of their target genes in a sequence-specific manner. Emerging evidence demonstrates that miRNAs are critical regulators of lipid synthesis, fatty acid oxidation and lipoprotein formation and secretion. Dysregulation of miRNAs disrupts gene regulatory network, leading to metabolic syndrome and its related diseases. In this review, we introduced epigenetic and transcriptional regulation of miRNAs expression. We emphasized on several representative miRNAs that are functionally involved into lipid metabolism, including miR-33/33(⁎), miR122, miR27a/b, miR378/378(⁎), miR-34a and miR-21. Understanding the function of miRNAs in lipid homeostasis may provide potential therapeutic strategies for fatty liver disease.

RESUMEN

UNLABELLED: Anaplastic thyroid cancer (ATC), a rare thyroid cancer with poor prognosis, is associated with insufficient function of the sodium iodide symporter (NIS). Estrogen-related receptor γ (ERRγ) is a member of the orphan nuclear receptors with important functions in cell development and homeostasis. However, there are no reports that demonstrate whether ERRγ is related to NIS function. Here, we evaluated the role of ERRγ in the regulation of NIS function in ATC cells using GSK5182, an inverse agonist of ERRγ. METHODS: Two ATC cell lines, BHT-101 and CAL62, were incubated with GSK5182 at various time points and doses. The NIS function in the ATC cells was serially assessed by their uptake of radioiodine. The effects of GSK5182 on ERRγ and the mitogen-activated protein (MAP) kinase pathway, as well as on NIS protein, were evaluated by immunoblot assay. To examine whether the GSK5182-induced NIS functional activity can be affected by inhibition of the MAP kinase pathway, the MAP kinase activity and levels of radioiodine uptake were determined after application of a mitogen-activated protein kinase kinase (MEK) inhibitor to GSK5182-treated cells. Finally, the cytotoxic effect of (131)I was determined by clonogenic assay. RESULTS: Treatment with GSK5182 resulted in dose- and time-dependent increases in iodide uptake in ATC cells, which were accompanied by both the downregulation of ERRγ protein and the activation of extracellular signal-regulated kinase (ERK) 1/2. Both the increased radioiodine uptake and ERK1/2 activation of ATC cells were completely inhibited by the specific MEK inhibitor. GSK5182 treatment enhanced the membrane localization of NIS in both ATC cell lines. Accordingly, preexposure to GSK5182 enhanced the cytotoxic effects of (131)I treatment in ATC cells. CONCLUSION: These findings suggest that the inverse agonist of ERRγ enhances the responsiveness of radioiodine therapy by modulating NIS function in ATC cells via the regulation of ERRγ and the MAP kinase signaling pathway.

Asunto(s)

Moduladores de los Receptores de Estrógeno/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteínas Quinasas Activadas por Mitógenos , Receptores de Estrógenos/efectos de los fármacos , Simportadores/metabolismo , Tamoxifeno/análogos & derivados , Carcinoma Anaplásico de Tiroides/metabolismo , Neoplasias de la Tiroides/metabolismo , Western Blotting , Línea Celular Tumoral , Humanos , Radioisótopos de Yodo/metabolismo , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Tamoxifeno/farmacología , Tamoxifeno/uso terapéutico , Ensayo de Tumor de Célula Madre

RESUMEN

Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related death in China. Deregulation of microRNA (miRNA) contributes to HCC development by influencing cell growth, apoptosis, migration or invasion. It has been proved that miR-940 plays important roles in various cancers. Here we investigated the role of miR-940 in HCC. We found that miR-940 was remarkably decreased in HCC tissues and cell lines. Importantly, lower miR-940 expression in HCC tissues significantly correlated with the reduced patient's survival rate. Overexpression of miR-940 inhibited HCC cell line growth and induced cell apoptosis, and vice versa. Estrogen-related receptor gamma (ESRRG) was targeted by miR-940, and suppression of ESRRG inhibited HCC cell lines growth and induced cell apoptosis. In conclusion, we found that a lower level of miR-940 in HCC promoted cellular proliferation via ESRRG, which may lead to the short survival period of HCC patients.

Asunto(s)

Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , MicroARNs/fisiología , Regiones no Traducidas 3' , Apoptosis , Secuencia de Bases , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Células Hep G2 , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Pronóstico , Interferencia de ARN , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo

RESUMEN

BACKGROUND: It is well known that peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) plays an important role in tissue energy metabolism. However, the roles of PGC-1α in malignant endometrial cancer remain unknown. METHODS: Forty cases of endometrial carcinoma, 15 cases with proliferative endometrial tissues, and 21 cases with normal endometrial tissues were collected. Real-time polymerase chain reaction was used to detect the mRNA levels of PGC-1α and estrogen-related receptor gamma (ERRγ). ELISA (enzyme-linked immunosorbent assay) was used to detect the concentrations of pyruvate kinase and isocitrate dehydrogenase. The results were analyzed using medical statistical methods. RESULTS: The mRNA levels of PGC-1α and ERRγ in the endometrial carcinoma tissues and hyperplasic endometrial tissues were significantly greater than those in the normal endometria. The mRNA levels of PGC-1α and ERRγ in the endometrial carcinoma patients with type 2 diabetes were higher than those in patients without diabetes. The mRNA levels of PGC-1α and ERRγ in the endometrial adenocarcinomas increased with clinical staging, depth of myometrial invasion, and increases in the number of metastatic lymph nodes. The PGC-1α mRNA level was positively correlated with ERRγ in the endometrial carcinoma tissues. The mRNA levels of PGC-1α were positively correlated with the concentrations of pyruvate kinase and isocitrate dehydrogenase in the endometrial carcinoma tissues, and similar results were found for ERRγ. CONCLUSION: Our results suggested that the upregulation of PGC-1α and ERRγ in endometrial cancer might be a requirement for cancer cell energy metabolism, which contributes to the development of endometrial cancer.