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A generalizable strategy with programmable site specificity for in situ profiling of histone modifications on unperturbed chromatin remains highly desirable but challenging. We herein developed a single-site-resolved multi-omics (SiTomics) strategy for systematic mapping of dynamic modifications and subsequent profiling of chromatinized proteome and genome defined by specific chromatin acylations in living cells. By leveraging the genetic code expansion strategy, our SiTomics toolkit revealed distinct crotonylation (e.g., H3K56cr) and ß-hydroxybutyrylation (e.g., H3K56bhb) upon short chain fatty acids stimulation and established linkages for chromatin acylation mark-defined proteome, genome, and functions. This led to the identification of GLYR1 as a distinct interacting protein in modulating H3K56cr's gene body localization as well as the discovery of an elevated super-enhancer repertoire underlying bhb-mediated chromatin modulations. SiTomics offers a platform technology for elucidating the "metabolites-modification-regulation" axis, which is widely applicable for multi-omics profiling and functional dissection of modifications beyond acylations and proteins beyond histones.
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Cromatina , Proteoma , Acilación , Mapeo Cromosómico , Histonas , Supervivencia CelularRESUMEN
Necroptosis induction in vitro often requires caspase-8 (Casp8) inhibition by zVAD because pro-Casp8 cleaves RIP1 to disintegrate the necrosome. It has been unclear how the Casp8 blockade of necroptosis is eliminated naturally. Here, we show that pro-Casp8 within the necrosome can be inactivated by phosphorylation at Thr265 (pC8T265). pC8T265 occurs in vitro in various necroptotic cells and in the cecum of TNF-treated mice. p90 RSK is the kinase of pro-Casp8. It is activated by a mechanism that does not need ERK but PDK1, which is recruited to the RIP1-RIP3-MLKL-containing necrosome. Phosphorylation of pro-Casp8 at Thr265 can substitute for zVAD to permit necroptosis in vitro. pC8T265 mimic T265E knockin mice are embryonic lethal due to unconstrained necroptosis, and the pharmaceutical inhibition of RSK-mediated pC8T265 diminishes TNF-induced cecum damage and lethality in mice by halting necroptosis. Thus, phosphorylation of pro-Casp8 at Thr265 by RSK is an intrinsic mechanism for passing the Casp8 checkpoint of necroptosis.
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Proteínas Quinasas Dependientes de 3-Fosfoinosítido/metabolismo , Caspasa 8/metabolismo , Necroptosis , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Transducción de Señal , Animales , Ciego/lesiones , Ciego/patología , Línea Celular , Embrión de Mamíferos/metabolismo , Desarrollo Embrionario/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Ratones Endogámicos C57BL , Mutación/genética , Necroptosis/efectos de los fármacos , Especificidad de Órganos , Fosforilación/efectos de los fármacos , Fosfotreonina/metabolismo , Proteínas Quinasas/metabolismo , Proteínas Quinasas S6 Ribosómicas 90-kDa/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Metalloregulators allosterically control transcriptional activity through metal binding-induced reorganization of ligand residues and/or hydrogen bonding networks, while the coordination atoms on the same ligand residues remain seldom changed. Here we show that the MarR-type zinc transcriptional regulator ZitR switches one of its histidine nitrogen atoms for zinc coordination during the allosteric control of DNA binding. The Zn(II)-coordination nitrogen on histidine 42 within ZitR's high-affinity zinc site (site 1) switches from Nε2 to Nδ1 upon Zn(II) binding to its low-affinity zinc site (site 2), which facilitates ZitR's conversion from the nonoptimal to the optimal DNA-binding conformation. This histidine switch-mediated cooperation between site 1 and site 2 enables ZitR to adjust its DNA-binding affinity in response to a broad range of zinc fluctuation, which may allow the fine tuning of transcriptional regulation.
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Histidina/química , Histidina/metabolismo , Zinc/metabolismo , Regulación Alostérica , Sitios de Unión , ADN/química , ADN/metabolismo , Espacio Intracelular/metabolismo , Cinética , Conformación Molecular , Relación Estructura-ActividadRESUMEN
Posttranslational modifications (PTMs) of lysine are crucial histone marks that regulate diverse biological processes. The functional roles and regulation mechanism of many newly identified lysine PTMs, however, remain yet to be understood. Here we report a photoaffinity crotonyl lysine (Kcr) analogue that can be genetically and site-specifically incorporated into histone proteins. This, in conjunction with the genetically encoded photo-lysine as a "control probe", enables the capture and identification of enzymatic machinery and/or effector proteins for histone lysine crotonylation.
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Histonas/química , Histonas/genética , Lisina/química , Etiquetas de Fotoafinidad/química , Código Genético , Histonas/metabolismo , Lisina/análogos & derivados , Lisina/metabolismo , Conformación Molecular , Etiquetas de Fotoafinidad/metabolismoRESUMEN
Multiple antibiotic resistance regulator (MarR) family proteins are widely conserved transcription factors that control bacterial resistance to antibiotics, environmental stresses, as well as the regulation of virulence determinants. Escherichia coli MarR, the prototype member of this family, has recently been shown to undergo copper(II)-catalyzed inter-dimer disulfide bond formation via a unique cysteine residue (Cys80) residing in its DNA-binding domain. However, despite extensive structural characterization of the MarR family proteins, the structural mechanism for DNA binding of this copper(II)-sensing MarR factor remains elusive. Here, we report the crystal structures of DNA-bound forms of MarR, which revealed a unique, concerted generation of two new helix-loop-helix motifs that facilitated MarR's DNA binding. Structural analysis and electrophoretic mobility shift assays (EMSA) show that the flexibility of Gly116 in the center of helix α5 and the extensive hydrogen-bonding interactions at the N-terminus of helix α1 together assist the reorientation of the wHTH domains and stabilize MarR's DNA-bound conformation.
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Cobre/química , ADN Bacteriano/química , Proteínas de Escherichia coli/química , Escherichia coli/química , Sitios de Unión , Cobre/metabolismo , ADN Bacteriano/metabolismo , Farmacorresistencia Microbiana , Ensayo de Cambio de Movilidad Electroforética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Modelos Moleculares , Estructura MolecularRESUMEN
The widely conserved multiple antibiotic resistance regulator (MarR) family of transcription factors modulates bacterial detoxification in response to diverse antibiotics, toxic chemicals or both. The natural inducer for Escherichia coli MarR, the prototypical transcription repressor within this family, remains unknown. Here we show that copper signaling potentiates MarR derepression in E. coli. Copper(II) oxidizes a cysteine residue (Cys80) on MarR to generate disulfide bonds between two MarR dimers, thereby inducing tetramer formation and the dissociation of MarR from its cognate promoter DNA. We further discovered that salicylate, a putative MarR inducer, and the clinically important bactericidal antibiotics norfloxacin and ampicillin all stimulate intracellular copper elevation, most likely through oxidative impairment of copper-dependent envelope proteins, including NADH dehydrogenase-2. This membrane-associated copper oxidation and liberation process derepresses MarR, causing increased bacterial antibiotic resistance. Our study reveals that this bacterial transcription regulator senses copper(II) as a natural signal to cope with stress caused by antibiotics or the environment.
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Cobre/metabolismo , Farmacorresistencia Microbiana , Proteínas de Escherichia coli/metabolismo , Escherichia coli/metabolismo , Proteínas Represoras/metabolismo , Modelos Moleculares , Transducción de SeñalRESUMEN
PURPOSE: To investigate the effect of SGLT2i on the GH/IGF1 axis in male patients with newly diagnosed type 2 diabetes (T2D). METHODS: Sixty male patients with newly diagnosed T2D were recruited, and randomly assigned to Metformin+SGLT2i group or Metformin group after baseline assessment. All patients received standard lifestyle interventions, and blood indices were obtained before and after 12 weeks of treatment. RESULTS: After 12 weeks of treatment with Metformin+SGLT2i, there were noteworthy improvements in patients' FPG (Fasting plasma glucose), HBA1c, HOMA-IR, HOMA-ß, TyG (Triglyceride-glucose) index and UACR (P < 0.05). Both IGF1 (P = 0.01) and the IGF1/IGFBP3 ratio (P < 0.01) considerably increased, while GH and IGFBP3 did not show significant changes. When comparing Metformin+SGLT2i group to Metformin group, SGLT2i significantly improved HOMA-IR [P = 0.04], and elevated IGF1/IGFBP3 ratio [P = 0.04], SGLT2i showed a tendency of increasing IGF1 (P = 0.10), but this was not statistically meaningful. There was no effect on GH and IGFBP3. Correlation analysis showed that blood IGF1 was negatively correlated with FPG, HBA1c, HOMA-IR, TyG index and positively correlated with IGFBP3. Regression analysis indicated that FPG and testosterone had a negative effect on blood IGF1 level, while HOMA-IR had no obvious effect. CONCLUSION: In male patients with newly diagnosed T2D, SGLT2i can increase IGF1/IGFBP3 ratio, alleviate insulin resistance, but has no significant effect on GH and IGF1 levels. Additionally, our study showed that Metformin+SGLT2i treatment resulted in an increase in blood IGF1 levels and improved insulin resistance, suggesting a potentially beneficial role of IGF1 in newly diagnosed T2D.
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Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Metformina , Humanos , Masculino , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hemoglobina Glucada , Estudios de Casos y Controles , Estudios Prospectivos , Glucemia/análisis , Metformina/uso terapéutico , Factor I del Crecimiento Similar a la InsulinaRESUMEN
Dysregulated eEF2K expression is implicated in the pathogenesis of many human cancers, including triple-negative breast cancer (TNBC), making it a plausible therapeutic target. However, specific eEF2K inhibitors with potent anti-cancer activity have not been available so far. Targeted protein degradation has emerged as a new strategy for drug discovery. In this study, a novel small molecule chemical is designed and synthesized, named as compound C1, which shows potent activity in degrading eEF2K. C1 selectively binds to F8, L10, R144, C146, E229, and Y236 of the eEF2K protein and promotes its proteasomal degradation by increasing the interaction between eEF2K and the ubiquitin E3 ligase ßTRCP in the form of molecular glue. C1 significantly inhibits the proliferation and metastasis of TNBC cells both in vitro and in vivo and in TNBC patient-derived organoids, and these antitumor effects are attributed to the degradation of eEF2K by C1. Additionally, combination treatment of C1 with paclitaxel, a commonly used chemotherapeutic drug, exhibits synergistic anti-tumor effects against TNBC. This study not only generates a powerful research tool to investigate the therapeutic potential of targeting eEF2K, but also provides a promising lead compound for developing novel drugs for the treatment of TNBC and other cancers.
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Quinasa del Factor 2 de Elongación , Neoplasias de la Mama Triple Negativas , Humanos , Línea Celular Tumoral , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Fosforilación , Transducción de Señal , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Quinasa del Factor 2 de Elongación/antagonistas & inhibidoresRESUMEN
Aporphine alkaloids embedded in 4H-dibenzo[de,g]quinoline four-ring structures belong to one of the largest subclasses of isoquinoline alkaloids. Aporphine is a privileged scaffold in the field of organic synthesis and medicinal chemistry for the discovery of new therapeutic agents for central nervous system (CNS) diseases, cancer, metabolic syndrome, and other diseases. In the past few decades, aporphine has attracted continuing interest to be widely used to develop selective or multitarget directed ligands (MTDLs) targeting the CNS (e.g., dopamine D1/2/5, serotonin 5-HT1A/2A/2C and 5-HT7, adrenergic α/ß receptors, and cholinesterase enzymes), thereby serving as valuable pharmacological probes for mechanism studies or as potential leads for CNS drug discovery. The aims of the present review are to highlight the diverse CNS activities of aporphines, discuss their SAR, and briefly summarize general synthetic routes, which will pave the way for the design and development of new aporphine derivatives as promising CNS active drugs in the future.
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Alcaloides , Aporfinas , Relación Estructura-Actividad , Serotonina , Aporfinas/farmacología , Aporfinas/química , Aporfinas/metabolismo , Alcaloides/química , Fármacos del Sistema Nervioso Central/farmacología , Descubrimiento de DrogasRESUMEN
RIP1 and RIP3, cell death mediators, form fibrous amyloids. How RIP1/RIP3 amyloidal oligomers assemble functional necrosomes and control cell death is largely unknown. Here we use super-resolution microscopy to directly visualize cellular necrosomes as mosaics of RIP1 and RIP3 oligomers. The small (initial) mosaic complexes are round, and the large mosaics are in a rod shape. RIP3 oligomers with sizes of tetramer or above are the domains in mosaics that allow MLKL, recruited by phosphorylated RIP3, to oligomerize for necroptosis. Unexpectedly, RIP1 autophosphorylation not only controls the ordered oligomerization of RIP1 but also is required for RIP1-initiated RIP3 homo-oligomerization in correct organization, which is indispensable for the formation of functional rod-shaped mosaics. Similarly, apoptosis initiated by enzymatically defective RIP3 requires the formation of rod-shaped mosaics of RIP3 and RIP1 oligomers. The revealing of nanoscale architecture of necrosomes here innovates our understanding of the structural and organizational basis of this signalling hub in cell death.
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Proteínas Quinasas , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Amiloide , Apoptosis/fisiología , Muerte Celular , Humanos , Necroptosis , Necrosis/metabolismo , Proteínas Quinasas/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Transducción de SeñalRESUMEN
Formaldehyde (FA) has long been considered as a toxin and carcinogen due to its damaging effects to biological macromolecules, but its beneficial roles have been increasingly appreciated lately. Real-time monitoring of this reactive molecule in living systems is highly desired in order to decipher its physiological and/or pathological functions, but a genetically encoded FA sensor is currently lacking. We herein adopt a structure-based study of the underlying mechanism of the FA-responsive transcription factor HxlR from Bacillus subtilis, which shows that HxlR recognizes FA through an intra-helical cysteine-lysine crosslinking reaction at its N-terminal helix α1, leading to conformational change and transcriptional activation. By leveraging this FA-induced intra-helical crosslinking and gain-of-function reorganization, we develop the genetically encoded, reaction-based FA sensor-FAsor, allowing spatial-temporal visualization of FA in mammalian cells and mouse brain tissues.
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Bacillus subtilis/metabolismo , Proteínas Bacterianas/metabolismo , Técnicas Biosensibles/métodos , Formaldehído/metabolismo , Factores de Transcripción/metabolismo , Animales , Proteínas Bacterianas/química , Encéfalo/metabolismo , Reactivos de Enlaces Cruzados/química , Cisteína/química , Cisteína/metabolismo , Formaldehído/análisis , Humanos , Lisina/química , Lisina/metabolismo , Ratones , Conformación Proteica , Reproducibilidad de los Resultados , Factores de Transcripción/químicaRESUMEN
Mn:0.15Pb(In1/2Nb1/2)O3-0.55Pb(Mg1/3Nb2/3)O3-0.30PbTiO3 (Mn:PIMNT) pyroelectric chips were prepared by a two-step annealing method. For the two steps, annealing temperatures dependence of microstructure, defects, surface stress, surface roughness, dielectric properties and pyroelectric properties were studied comprehensively. The controlling factors influencing the pyroelectric properties of the Mn:PIMNT crystals were analyzed and the optimum annealing temperature ranges for the two steps were determined: 600-700 °C for the first step and 500-600 °C for the second step. The pyroelectric properties of the thin Mn:PIMNT chips were significantly enhanced by the two-step annealing method via tuning oxygen vacancies and eliminating surface stress. Based on Mn:PIMNT pyroelectric chips annealed at the most favorable conditions (annealed at 600 °C for the first step and 500 °C for the second step), infrared detectors were prepared with specific detectivity D* = 1.63 × 109 cmHz1/2W-1, nearly three times higher than in commercial LiTaO3 detectors.
RESUMEN
Great progress has been made in expanding the repertoire of genetically encoded fluorescent sensors for monitoring intracellular transition metals (TMs). This powerful toolkit permits dynamic and non-invasive detection of TMs with high spatial-temporal resolution, which enables us to better understand the roles of TM homeostasis in both physiological and pathological settings. Here we summarize the recent development of genetically encoded fluorescent sensors for intracellular detection of TMs such as zinc and copper, as well as heavy metals including lead, cadmium, mercury, and arsenic.
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Técnicas Biosensibles , Colorantes Fluorescentes/química , Proteínas Luminiscentes/química , Proteínas Luminiscentes/genética , Metales Pesados/análisis , Elementos de Transición/análisis , Homeostasis , HumanosRESUMEN
The 1 wt % Li-doped (Ba0.85Ca0.15)(Zr0.1Ti0.9)O3 (BCZT-Li) ceramics prepared by the citrate method exhibit improved phase purity, densification and electrical properties, which provide prospective possibility to develop high-performance electrocaloric materials. The electrocaloric effect was evaluated by phenomenological method, and the BCZT-Li ceramics present large electrocaloric temperature change ∆T, especially large electrocaloric responsibility ξ = ∆Tmax/∆Emax, which can be comparable to the largest values reported in the lead-free piezoelectric ceramics. The excellent electrocaloric effect is considered as correlating with the coexistence of polymorphic ferroelectric phases, which are detected by the Raman spectroscopy. The large ξ value accompanied by decreased Curie temperature (around 73 °C) of the BCZT-Li ceramics prepared by the citrate method presents potential applications as the next-generation solid-state cooling devices.
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Astragaloside IV is a monomer isolated from Astragalus membranaceus (Fisch.) Bunge, which is one of the most widely used plant-derived drugs in traditional Chinese medicine for diabetes therapy. In the present study, we aimed to examine the effects of astragaloside IV on glucose in C2C12 myotubes and the underlying molecular mechanisms responsible for these effects. Four-day differentiated C2C12 myotubes were exposed to palmitate for 16 h in order to establish a model of insulin resistance and 3H glucose uptake, using 2-DeoxyD[1,2-3H(N)]-glucose (radiolabeled 2-DG), was detected. Astragaloside IV was added 2 h prior to palmitate exposure. The translocation of glucose transporter 4 (GLUT4) was evaluated by subcellular fractionation, and the expression of insulin signaling molecules such as insulin receptor ß (IRß), insulin receptor substrate (IRS)1/protein kinase B (AKT) and inhibitory κB kinase (IKK)/inhibitor-κBα (IκBα), which are associated with insulin signal transduction, were assessed in the basal or the insulinstimulated state using western blot analysis or RT-PCR. We also examined the mRNA expression of monocyte chemotactic protein 1 (MCP-1), interleukin 6 (IL-6), tumor necrosis factor α (TNFα) and Tolllike receptor 4 (TLR4). Taken together, these findings demonstrated that astragaloside IV facilitates glucose transport in C2C12 myotubes through a mechanism involving the IRS1/AKT pathway, and suppresses the palmitate-induced activation of the IKK/IκBα pathway.
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Regulación de la Expresión Génica/efectos de los fármacos , Glucosa/agonistas , Hipoglucemiantes/farmacología , Fibras Musculares Esqueléticas/efectos de los fármacos , Ácido Palmítico/antagonistas & inhibidores , Saponinas/farmacología , Triterpenos/farmacología , Animales , Transporte Biológico/efectos de los fármacos , Línea Celular , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Glucosa/metabolismo , Transportador de Glucosa de Tipo 4/genética , Transportador de Glucosa de Tipo 4/metabolismo , Quinasa I-kappa B/genética , Quinasa I-kappa B/metabolismo , Proteínas Sustrato del Receptor de Insulina/genética , Proteínas Sustrato del Receptor de Insulina/metabolismo , Resistencia a la Insulina , Interleucina-6/genética , Interleucina-6/metabolismo , Ratones , Modelos Biológicos , Fibras Musculares Esqueléticas/citología , Fibras Musculares Esqueléticas/metabolismo , Inhibidor NF-kappaB alfa/genética , Inhibidor NF-kappaB alfa/metabolismo , Ácido Palmítico/farmacología , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Heme plays pivotal roles in various cellular processes as well as in iron homeostasis in living systems. Here, we report a genetically encoded fluorescence resonance energy transfer (FRET) sensor for selective heme imaging by employing a pair of bacterial heme transfer chaperones as the sensory components. This heme-specific probe allows spatial-temporal visualization of intracellular heme distribution within living cells.
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Técnicas Biosensibles/métodos , Transferencia Resonante de Energía de Fluorescencia/métodos , Hemo/análisis , Animales , Bacillus anthracis/genética , Bacillus anthracis/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Línea Celular , Línea Celular Tumoral , Cricetinae , Ingeniería Genética , Hemo/metabolismo , Humanos , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Ratones , Imagen Óptica/métodosRESUMEN
BACKGROUND: Emodin, the major bioactive component of Rheum palmatum, has many different activities, including antitumor, anti-inflammatory, and antidiabetes effects. Recently, emodin was reported to regulate energy metabolism. In the present study, we further explored the effects of emodin on glucose and lipid metabolism. METHODS: Differentiated C2C12 myotubes and 3T3-L1 adipocytes were treated with or without different concentrations of emodin (6.25, 12.5, 25 or 50 µmol/L) for different time (1 h, 3 h, 12 h, 24 h or 48 h). Glucose metabolism, oxygen consumption, lactic acid levels, glycerol levels, and inflammation pathways were then evaluated. Cells were collected for quantitative polymerase chain reaction (PCR) and western blot analysis. RESULTS: Emodin upregulated glucose uptake and consumption in both C2C12 myotubes and 3T3-L1 adipocytes, with glycolysis increased. Furthermore, emodin inhibited lipolysis under basal conditions (as well as in the presence of 10 ng/ml tumor necrosis factor (TNF-)-α in 3T3-L1 adipocytes) and significantly decreased phosphorylated perilipin. Moreover, emodin inhibited the nuclear factor-κB and extracellular signal-regulated kinase pathways in C2C12 myotubes and 3T3-L1 adipocytes. CONCLUSIONS: Emodin upregulates glucose metabolism, decreases lipolysis, and inhibits inflammation in C2C12 myotubes and 3T3-L1 adipocytes.
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Adipocitos/efectos de los fármacos , Emodina/farmacología , Metabolismo Energético/efectos de los fármacos , Glucosa/metabolismo , Inflamación/prevención & control , Lipólisis/efectos de los fármacos , Fibras Musculares Esqueléticas/efectos de los fármacos , Células 3T3-L1 , Adipocitos/citología , Adipocitos/inmunología , Animales , Western Blotting , Células Cultivadas , Ensayo de Cambio de Movilidad Electroforética , Técnicas In Vitro , Inflamación/inmunología , Inflamación/metabolismo , Ratones , Fibras Musculares Esqueléticas/citología , Fibras Musculares Esqueléticas/inmunología , Consumo de Oxígeno/efectos de los fármacos , Fosforilación/efectos de los fármacos , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Chemerin is an adipokine involved in obesity, inflammation, and innate immune system that is highly expressed in the liver. In the present study, we find that chemerin mRNA expression is decreased in the livers of rodents with nonalcoholic fatty liver disease as well as in HepG2 cells after lipid overloading. Moreover, we report that chemerin expression and secretion are induced in HepG2 cells and primary hepatocytes from wild-type mice, but not farnesoid X receptor (FXR)-/- mice, in response to the synthetic FXR ligand GW4064. Hepatic chemerin expression is decreased in FXR-/- mice but up-regulated by GW4064 administration in wild-type mice. Dual-luciferase reporter assay and chromatin immunoprecipitation analyses further identified a functional FXR response element located in the -258-bp /+121-bp region of the chemerin gene. These data demonstrate that chemerin, a novel target gene of FXR, is related to nonalcoholic steatohepatitis.