RESUMEN
Knockout of ERß in the mouse leads to nuclear expression of epidermal growth factor receptor (EGFR) in the prostate. To examine whether ERß plays a similar role in the human prostate, we used four cohorts of men: 1) a Swedish cohort of normal prostates and PCa (prostate cancer) of different Gleason grades; 2) men with benign prostatic hyperplasia (BPH) treated with the 5α-reductase inhibitor, finasteride, and finasteride together with the ERß agonists, soy isoflavones; 3) men with PCa above Gleason grade 4 (GG4), treated with ADT (androgen deprivation therapy) and abiraterone (AA), the blocker of androgen synthesis for different durations; and 4) men with GG4 PCa on ADT or ADT with the AR (androgen receptor) blocker, enzalutamide, for 4 mo to 6 mo. In men with BPH, finasteride treatment induced EGFR nuclear expression, but, when finasteride was combined with isoflavones, EGFR remained on the cell membrane. In GG4 patients, blocking of AR for 4 mo to 6 mo resulted in loss of ERß and PTEN expression and increase in patients with nuclear EGFR from 10 to 40%. In the men with GG4 PCa, blocking of adrenal synthesis of testosterone for 2 mo to 7 mo had the beneficial effect of increasing ERß expression, but, on treatment longer than 8 mo, ERß was lost and EGFR moved to the nucleus. Since nuclear EGFR is a predictor of poor outcome in PCa, addition of ERß agonists together with abiraterone should be considered as a treatment that might sustain expression of ERß and offer some benefit to patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Receptor beta de Estrógeno/agonistas , Hiperplasia Prostática/tratamiento farmacológico , Neoplasias de la Próstata/tratamiento farmacológico , Transporte Activo de Núcleo Celular/efectos de los fármacos , Antagonistas de Andrógenos/farmacología , Antagonistas de Andrógenos/uso terapéutico , Androstenos/farmacología , Androstenos/uso terapéutico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzamidas/farmacología , Benzamidas/uso terapéutico , Biopsia , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Estudios de Cohortes , Receptores ErbB/metabolismo , Receptor beta de Estrógeno/metabolismo , Finasterida/farmacología , Finasterida/uso terapéutico , Humanos , Masculino , Ratones , Ratones Noqueados , Clasificación del Tumor , Nitrilos/farmacología , Nitrilos/uso terapéutico , Fosfohidrolasa PTEN/metabolismo , Feniltiohidantoína/farmacología , Feniltiohidantoína/uso terapéutico , Fitoestrógenos/farmacología , Fitoestrógenos/uso terapéutico , Próstata/citología , Próstata/efectos de los fármacos , Próstata/patología , Hiperplasia Prostática/patología , Neoplasias de la Próstata/patología , Receptores Androgénicos/metabolismo , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismoRESUMEN
Disagreements about the phenotype of estrogen receptor ß (ERß) knockout mouse, created by removing the DNA-binding domain of the ERß gene or interruption of the gene with a neocassette (Oliver Smithies ERß knockout mice [ERßOS-/-]), prompted us to create an ERß knockout mouse by deleting the ERß gene with the use of CRISPR/Cas9 technology. We confirmed that the ERß gene was eliminated from the mouse genome and that no ERß mRNA or protein was detectable in tissues of this mouse. Overall the phenotype of the ventral prostate (VP) and mammary gland (MG) in ERßcrispr-/- mice was similar to, but more severe than, that in the ERßOS-/-mice. In the VP of 6-mo-old ERßcrispr-/- mice there was epithelial hyperplasia, fibroplasia, inflammation, stromal overgrowth, and intraductal cancer-like lesions. This was accompanied by an increase in Ki67 and P63 and loss in DACH1 and PURα, two androgen receptor (AR) repressors. In the MG there was overexpression of estrogen receptor α and progesterone receptor, loss of collagen, increase in proliferation and expression of metalloproteases, and invasive epithelium. Surprisingly, by 18 mo of age, the number of hyperplastic foci was reduced, the ducts of the VP and MG became atrophic, and, in the VP, there was massive immune infiltration and massive desquamation of the luminal epithelial cells. These changes were coincident with reduced levels of androgens in males and estrogens in females. We conclude that ERß is a tumor suppressor gene in the VP and MG where its loss increases the activity AR and ERα, respectively.
Asunto(s)
Receptor beta de Estrógeno/genética , Glándulas Mamarias Animales/metabolismo , Fenotipo , Próstata/metabolismo , Receptores Androgénicos/metabolismo , Eliminación de Secuencia , Andrógenos/metabolismo , Animales , Sistemas CRISPR-Cas , Quimiocinas/metabolismo , Proteínas de Unión al ADN/metabolismo , Epitelio/metabolismo , Receptor alfa de Estrógeno/metabolismo , Estrógenos/metabolismo , Proteínas del Ojo , Femenino , Hiperplasia/patología , Inflamación , Antígeno Ki-67/metabolismo , Masculino , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/metabolismo , Próstata/patología , ARN Mensajero/metabolismo , Transducción de Señal , Células del Estroma , Transactivadores , Factores de Transcripción/metabolismo , Transcriptoma , Proteínas Supresoras de Tumor/metabolismoRESUMEN
The retina is an extension of the brain. Like the brain, neurodegeneration of the retina occurs with age and is the cause of several retinal diseases including optic neuritis, macular degeneration, and glaucoma. Liver X receptors (LXRs) are expressed in the brain where they play a key role in maintenance of cerebrospinal fluid and the health of dopaminergic neurons. Herein, we report that LXRs are expressed in the retina and optic nerve and that loss of LXRß, but not LXRα, leads to loss of ganglion cells in the retina. In the retina of LXRß-/- mice, there is an increase in amyloid A4 and deposition of beta-amyloid (Aß) aggregates but no change in the level of apoptosis or autophagy in the ganglion cells and no activation of microglia or astrocytes. However, in the optic nerve there is a loss of aquaporin 4 (AQP4) in astrocytes and an increase in activation of microglia. Since loss of AQP4 and microglial activation in the optic nerve precedes the loss of ganglion cells, and accumulation of Aß in the retina, the cause of the neuronal loss appears to be optic nerve degeneration. In patients with optic neuritis there are frequently AQP4 autoantibodies which block the function of AQP4. LXRß-/- mouse is another model of optic neuritis in which AQP4 antibodies are not detectable, but AQP4 function is lost because of reduction in its expression.
Asunto(s)
Receptores X del Hígado/deficiencia , Degeneración Nerviosa/patología , Nervio Óptico/patología , Retina/patología , Péptidos beta-Amiloides/metabolismo , Animales , Acuaporina 4/metabolismo , Astrocitos/metabolismo , Astrocitos/patología , Femenino , Receptores X del Hígado/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Degeneración Nerviosa/metabolismo , Neuroglía/metabolismo , Neuroglía/patología , Oligodendroglía/metabolismo , Nervio Óptico/metabolismo , Retina/metabolismo , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patologíaRESUMEN
BACKGROUND: Male estrogen receptor beta (ERß) knockout (BERKO) mice display anxiety and aggression linked to, among others, altered serotonergic signaling in the basolateral amygdala and dorsal raphe, impaired cortical radial glia migration, and reduced GABAergic signaling. The effects on primary motor cortex (M1 cortex) and locomotor activity as a consequence of ERß loss have not been investigated. OBJECTIVE: The aim of this study was to determine whether locomotor activity is altered as a consequence of the changes in the M1 cortex. METHODS: The locomotor activity of male wild-type (WT) and BERKO mice was evaluated using the open-field and rotarod tests. Molecular changes in the M1 cortex were analyzed by RNA sequencing, electron microscopy, electrophysiology, and immunohistological techniques. In addition, we established oligodendrocyte (OL) cultures from WT and BERKO mouse embryonic stem cells to evaluate OL function. RESULTS: Locomotor profiling revealed that BERKO mice were more active than WT mice but had impaired motor coordination. Analysis of the M1 cortex pointed out differences in synapse function and myelination. There was a reduction in GABAergic signaling resulting in imbalanced excitatory and inhibitory neurotransmission as well as a defective OL differentiation accompanied by myelin defects. The effects of ERß loss on OL differentiation were confirmed in vitro. CONCLUSION: ERß is an important regulator of GABAergic interneurons and OL differentiation, which impacts on adult M1 cortex function and may be linked to increased locomotor activity and decreased motor coordination in BERKO mice.
Asunto(s)
Receptor beta de Estrógeno/genética , Locomoción/genética , Corteza Motora/fisiopatología , Vaina de Mielina/fisiología , Desempeño Psicomotor , Transmisión Sináptica , Animales , Expresión Génica , Masculino , Ratones , Ratones Noqueados , Corteza Motora/metabolismo , Oligodendroglía/patologíaRESUMEN
As estrogen receptor ß-/- (ERß-/-) mice age, the ventral prostate (VP) develops increased numbers of hyperplastic, fibroplastic lesions and inflammatory cells. To identify genes involved in these changes, we used RNA sequencing and immunohistochemistry to compare gene expression profiles in the VP of young (2-mo-old) and aging (18-mo-old) ERß-/- mice and their WT littermates. We also treated young and old WT mice with an ERß-selective agonist and evaluated protein expression. The most significant findings were that ERß down-regulates androgen receptor (AR) signaling and up-regulates the tumor suppressor phosphatase and tensin homolog (PTEN). ERß agonist increased expression of the AR corepressor dachshund family (DACH1/2), T-cadherin, stromal caveolin-1, and nuclear PTEN and decreased expression of RAR-related orphan receptor c, Bcl2, inducible nitric oxide synthase, and IL-6. In the ERß-/- mouse VP, RNA sequencing revealed that the following genes were up-regulated more than fivefold: Bcl2, clusterin, the cytokines CXCL16 and -17, and a marker of basal/intermediate cells (prostate stem cell antigen) and cytokeratins 4, 5, and 17. The most down-regulated genes were the following: the antioxidant gene glutathione peroxidase 3; protease inhibitors WAP four-disulfide core domain 3 (WFDC3); the tumor-suppressive genes T-cadherin and caveolin-1; the regulator of transforming growth factor ß signaling SMAD7; and the PTEN ubiquitin ligase NEDD4. The role of ERß in opposing AR signaling, proliferation, and inflammation suggests that ERß-selective agonists may be used to prevent progression of prostate cancer, prevent fibrosis and development of benign prostatic hyperplasia, and treat prostatitis.
Asunto(s)
Envejecimiento/metabolismo , Regulación hacia Abajo , Receptor beta de Estrógeno/metabolismo , Próstata/metabolismo , Receptores Androgénicos/biosíntesis , Transducción de Señal , Envejecimiento/genética , Envejecimiento/patología , Andrógenos/metabolismo , Animales , Quimiocina CXCL16/biosíntesis , Quimiocina CXCL16/genética , Quimiocinas CXC/biosíntesis , Quimiocinas CXC/genética , Clusterina/biosíntesis , Clusterina/genética , Receptor beta de Estrógeno/genética , Interleucina-6/genética , Interleucina-6/metabolismo , Queratinas/biosíntesis , Queratinas/genética , Masculino , Ratones , Ratones Noqueados , Ubiquitina-Proteína Ligasas Nedd4/biosíntesis , Ubiquitina-Proteína Ligasas Nedd4/genética , Fosfohidrolasa PTEN/biosíntesis , Fosfohidrolasa PTEN/genética , Próstata/patología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Receptores Androgénicos/genética , Proteína smad7/biosíntesis , Proteína smad7/genéticaRESUMEN
The etiology of peripheral squamous cell lung cancer (PSCCa) remains unknown. Here, we show that this condition spontaneously develops in mice in which the genes for two oxysterol receptors, Liver X Receptor (LXR) α (Nr1h3) and ß (Nr1h2), are inactivated. By 1 y of age, most of these mice have to be euthanized because of severe dyspnea. Starting at 3 mo, the lungs of LXRα,ß(Dko) mice, but not of LXRα or LXRß single knockout mice, progressively accumulate foam cells, so that by 1 y, the lungs are covered by a "golden coat." There is infiltration of inflammatory cells and progressive accumulation of lipid in the alveolar wall, type 2 pneumocytes, and macrophages. By 14 mo, there are three histological lesions: one resembling adenomatous hyperplasia, one squamous metaplasia, and one squamous cell carcinoma characterized by expression of transformation-related protein (p63), sex determining region Y-box 2 (Sox2), cytokeratin 14 (CK14), and cytokeratin 13 (CK13) and absence of thyroid transcription factor 1 (TTF1), and prosurfactant protein C (pro-SPC). RNA sequencing analysis at 12 mo confirmed a massive increase in markers of M1 macrophages and lymphocytes. The data suggest a previously unidentified etiology of PSCCa: cholesterol dysregulation and M1 macrophage-predominant lung inflammation combined with damage to, and aberrant repair of, lung tissue, particularly the peripheral parenchyma. The results raise the possibility that components of the LXR signaling may be useful targets in the treatment of PSCCa.
Asunto(s)
Metabolismo de los Lípidos , Receptores X del Hígado/fisiología , Neoplasias Pulmonares/etiología , Pulmón/metabolismo , Neoplasias de Células Escamosas/etiología , Células Epiteliales Alveolares/metabolismo , Animales , Fibroblastos/metabolismo , Homeostasis , Pulmón/patología , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Neumonía/etiología , Análisis de Secuencia de ARNRESUMEN
A therapeutic goal in the treatment of certain CNS diseases, including multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson disease, is to down-regulate inflammatory pathways. Inflammatory molecules produced by microglia are responsible for removal of damaged neurons, but can cause collateral damage to normal neurons located close to defective neurons. Although estrogen can inactivate microglia and inhibit the recruitment of T cells and macrophages into the CNS, there is controversy regarding which of the two estrogen receptors (ERs), ERα or ERß, mediates the beneficial effects in microglia. In this study, we found that ERß, but not ERα, is expressed in microglia. Using the experimental autoimmune encephalomyelitis (EAE) model in SJL/J mice, we evaluated the benefit of an ERß agonist as a modulator of neuroinflammation. Treatment of EAE mice with LY3201, a selective ERß agonist provided by Eli Lilly, resulted in marked reduction of activated microglia in the spinal cord. LY3201 down-regulated the nuclear transcription factor NF-κB, as well as the NF-κB-induced gene inducible nitric oxide synthase in microglia and CD3(+) T cells. In addition, LY3201 inhibited T-cell reactivity through regulation of indoleamine-2,3-dioxygenase. In the EAE model, treatment with LY3201 decreased mortality in the first 2 wk after disease onset, and also reduced the severity of symptoms in mice surviving for 4 wk. Our data show that ERß-selective agonists, by modulating the immune system in both microglia and T cells, offer promise as a useful class of drugs for treating degenerative diseases of the CNS.
Asunto(s)
Benzopiranos/uso terapéutico , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/inmunología , Receptor beta de Estrógeno/metabolismo , Microglía/metabolismo , Terapia Molecular Dirigida , Linfocitos T/metabolismo , Animales , Benzopiranos/farmacología , Regulación hacia Abajo/efectos de los fármacos , Encefalomielitis Autoinmune Experimental/enzimología , Encefalomielitis Autoinmune Experimental/patología , Receptor alfa de Estrógeno/metabolismo , Femenino , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Ratones , Microglía/efectos de los fármacos , Microglía/patología , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Médula Espinal/efectos de los fármacos , Médula Espinal/enzimología , Médula Espinal/patología , Linfocitos T/efectos de los fármacos , Linfocitos T/patologíaRESUMEN
Anxiety disorders are the most prevalent mental disorders in adolescents in the United States. Female adolescents are more likely than males to be affected with anxiety disorders, but less likely to have behavioral and substance abuse disorders. The prefrontal cortex (PFC), amygdala, and dorsal raphe are known to be involved in anxiety disorders. Inhibitory input from the PFC to the amygdala controls fear and anxiety typically originating in the amygdala, and disruption of the inhibitory input from the PFC leads to anxiety, fear, and personality changes. Recent studies have implicated liver X receptor ß (LXRß) in key neurodevelopmental processes and neurodegenerative diseases. In the present study, we used elevated plus-maze, startle and prepulse inhibition, open field, and novel object recognition tests to evaluate behavior in female LXRß KO (LXRß(-/-)) mice. We found that the female LXRß(-/-) mice were anxious with impaired behavioral responses but normal locomotion and memory. Immunohistochemistry analysis revealed decreased expression of the enzyme responsible for GABA synthesis, glutamic acid decarboxylase (65+67), in the ventromedial PFC. Expression of tryptophan hydroxylase 2 in the dorsal raphe was normal. We conclude that the anxiogenic phenotype in female LXRß(-/-) mice is caused by reduced GABAergic input from the ventromedial PFC to the amygdala.
Asunto(s)
Ansiedad/psicología , Glutamato Descarboxilasa/metabolismo , Receptores Nucleares Huérfanos/deficiencia , Corteza Prefrontal/enzimología , Adolescente , Animales , Ansiedad/fisiopatología , Miedo/fisiología , Miedo/psicología , Femenino , Humanos , Inmunohistoquímica , Receptores X del Hígado , Masculino , Aprendizaje por Laberinto/fisiología , Memoria/fisiología , Ratones , Ratones Noqueados , Actividad Motora/fisiología , Receptores Nucleares Huérfanos/genética , Receptores Nucleares Huérfanos/fisiología , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiopatología , Factores Sexuales , Ácido gamma-Aminobutírico/biosíntesisRESUMEN
Parkinson disease (PD) is a progressive neurodegenerative disease whose progression may be slowed, but at present there is no pharmacological intervention that would stop or reverse the disease. Liver X receptor ß (LXRß) is a member of the nuclear receptor super gene family expressed in the central nervous system, where it is important for cortical layering during development and survival of dopaminergic neurons throughout life. In the present study we have used the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD to investigate the possible use of LXRß as a target for prevention or treatment of PD. The dopaminergic neurons of the substantia nigra of LXRß(-/-) mice were much more severely affected by MPTP than were those of their WT littermates. In addition, the number of activated microglia and GFAP-positive astrocytes was higher in the substantia nigra of LXRß(-/-) mice than in WT littermates. Administration of the LXR agonist GW3965 to MPTP-treated WT mice protected against loss of dopaminergic neurons and of dopaminergic fibers projecting to the striatum, and resulted in fewer activated microglia and astroglia. Surprisingly, LXRß was not expressed in the neurons of the substantia nigra but in the microglia and astroglia. We conclude that LXR agonists may have beneficial effects in treatment of PD by modulating the cytotoxic functions of microglia.
Asunto(s)
Neuronas Dopaminérgicas/metabolismo , Receptores Nucleares Huérfanos/metabolismo , Trastornos Parkinsonianos/metabolismo , Sustancia Negra/citología , Análisis de Varianza , Animales , Astrocitos/metabolismo , Benzoatos/farmacología , Bencilaminas/farmacología , Proteína Ácida Fibrilar de la Glía , Inmunohistoquímica , Receptores X del Hígado , Masculino , Ratones , Ratones Noqueados , Microglía/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Receptores Nucleares Huérfanos/antagonistas & inhibidores , Receptores Nucleares Huérfanos/genética , Trastornos Parkinsonianos/prevención & control , Trastornos Parkinsonianos/terapiaRESUMEN
An estrogen receptor (ER) ß ligand (LY3201) with a preference for ERß over ERα was administered in s.c. pellets releasing 0.04 mg/d. The brains of these mice were examined 3 d after treatment had begun. Although estradiol-17ß is known to increase spine density and glutaminergic signaling, as measured by Golgi staining, a clear reduction in spines was evident on the dendritic branches in LY3201-treated mice but no morphological alteration and no difference in the number of dendritic spines on dendritic stems were observed. In the LY3201-treatment group, there was higher expression of glutamic acid decarboxylase (GAD) in layer V of cortex and in the CA1 of hippocampus, more GAD(+) terminals surrounding the pyramidal neurons and less glutamate receptor (NMDAR) on the neurons in layer V. There were no alterations in expression of Iba1 or in Olig2 or CNPase. However, GFAP(+) astrocytes were increased in the LY3201-treatment group. There were also more projections characteristic of activated astrocytes and increased expression of glutamine synthetase (GS). No expression of ERß was detectable in the nuclei of astrocytes. Clearly, LY3201 caused a shift in the balance between excitatory and inhibitory neurotransmission in favor of inhibition. This shift was due in part to increased synthesis of GABA and increased removal of glutamate from the synaptic cleft by astrocytes. The data reveal that treatment with a selective ERß agonist results in changes opposite to those reported in estradiol-17ß-treated mice and suggests that ERα and ERß play opposing roles in the brain.
Asunto(s)
Benzopiranos/farmacología , Encéfalo/efectos de los fármacos , Espinas Dendríticas/efectos de los fármacos , Receptor beta de Estrógeno/efectos de los fármacos , Transducción de Señal , Ácido gamma-Aminobutírico/metabolismo , Animales , Encéfalo/metabolismo , Espinas Dendríticas/metabolismo , Receptor beta de Estrógeno/metabolismo , Ligandos , Ratones , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
Age-related hearing loss is the most common type of hearing impairment, and is typically characterized by the loss of spiral ganglion neurons (SGNs). The two Liver X receptors (LXRs) are oxysterol-activated nuclear receptors which in adults, regulate genes involved in cholesterol homeostasis and modulation of macrophage activity. LXRß plays a key role in maintenance of health of dopaminergic neurons in the substantia nigra, large motor neurons in the spinal cord, and retinal ganglion cells in adult mice. We now report that LXRß is expressed in the SGNs of the cochlea and that loss of LXRß leads to age-related cochlea degeneration. We found that in the cochlea of LXRß-/- mice, there is loss of SGNs, activation of macrophages, demyelination in the spiral ganglion, decrease in glutamine synthetase (GS) expression and increase in glutamate accumulation in the cochlea. Part of the cause of damage to the SGNs might be glutamate toxicity which is known to be very toxic to these cells. Our study provides a so far unreported role of LXRß in maintenance of SGNs whose loss is a very common cause of hearing impairment.
Asunto(s)
Pérdida Auditiva , Receptores X del Hígado , Ganglio Espiral de la Cóclea , Animales , Ratones , Cóclea/fisiología , Glutamatos/metabolismo , Pérdida Auditiva/metabolismo , Receptores X del Hígado/genética , Receptores X del Hígado/metabolismo , Macrófagos , Neuronas/metabolismo , Ganglio Espiral de la Cóclea/metabolismoRESUMEN
We aimed to develop a double-injection model of intracerebral hemorrhage (ICH) in rabbits and to evaluate it as a tool for investigating post-ICH brain injury. Rabbits were injected with 300microL fresh autologous whole blood into the right basal ganglia. Behavioral changes were rated, brain water content (BWC) was measured and brain tissue morphology was also examined. ICH was established in 93.5% of the blood injection group. At 1, 3 and 7 days after ICH, there were significant differences in the total neurological scores (p<0.01) and BWC (p<0.01) between a sham-operated group and the ICH group. These findings suggest that the model produces a persistent neurological deficit, hematoma volume and perihematomal edema and closely mimics human hypertensive basal ganglia ICH; it is a controllable and reproducible hematoma that lends itself to quantitative investigation.
Asunto(s)
Hemorragia Cerebral , Modelos Animales de Enfermedad , Animales , Hemorragia de los Ganglios Basales/patología , Hemorragia de los Ganglios Basales/fisiopatología , Conducta Animal , Coagulación Sanguínea/fisiología , Edema Encefálico/etiología , Hemorragia Cerebral/complicaciones , Hemorragia Cerebral/etiología , Hemorragia Cerebral/patología , Estado de Conciencia/fisiología , Inyecciones , Masculino , Actividad Motora/fisiología , Enfermedades del Sistema Nervioso/etiología , Conejos , Factores de TiempoRESUMEN
Proinflammatory processes in adipose tissue contribute to development of breast cancer and insulin resistance. Crown-like structures (CLS) are histologic hallmarks of the proinflammatory process in adipose tissue. CLS are microscopic foci of dying adipocytes surrounded by macrophages mostly derived from monocytes in blood. Estrogen receptor ß (ERß) is expressed in microglia, macrophages within the central nervous system (CNS), where it evokes an anti-inflammatory response. The present study investigates the function of ERß in macrophages within CLS. We report that even though monocytes in the blood have no detectable levels of ERß, macrophages in CLS do express ERß. In ERß-/- mice, there was a significant increase in the number of CLS in both subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). CLS in these mice were dominated by pro-inflammatory macrophages (M1 macrophages) with higher expression of osteopontin (OPN) and an increase in number of proliferating macrophages. In mice made obese by Western diet, treatment with an ERß selective agonist (LY3201) reduced the number of CLS in both SAT and VAT with downregulation of OPN, activated hypoxia-inducible factor-1α (HIF-1α), proliferation and upregulation prolyl hydroxylase 2 (PHD2), the enzyme which prevents activation of HIF1α, in macrophages. We conclude that ERß expression is induced in macrophages in CLS within adipose tissue where it plays a pivotal role in suppression of CLS. Thus ERß agonists may be used to alleviate CLS-related breast cancer and insulin resistance in adipose tissue.
Asunto(s)
Tejido Adiposo/metabolismo , Receptor beta de Estrógeno/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Macrófagos/metabolismo , Osteopontina/metabolismo , Tejido Adiposo/patología , Animales , Receptor beta de Estrógeno/genética , Femenino , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Macrófagos/patología , Masculino , Ratones , Ratones Noqueados , Osteopontina/genéticaRESUMEN
Bimetallic macrocyclic complexes have attracted the attention of chemists and various organic ligands have been used as molecular building blocks, but supramolecular complexes based on semi-rigid organic ligands containing 1,2,4-triazole have remained rare until recently. It is easier to obtain novel topologies by making use of asymmetric semi-rigid ligands in the self-assembly process than by making use of rigid ligands. A new semi-rigid ligand, 3-[(pyridin-4-ylmethyl)sulfanyl]-5-(quinolin-2-yl)-4H-1,2,4-triazol-4-amine (L), has been synthesized and used to generate two novel bimetallic macrocycle complexes, namely bis{µ-3-[(pyridin-4-ylmethyl)sulfanyl]-5-(quinolin-2-yl)-4H-1,2,4-triazol-4-amine}bis[(methanol-κO)(nitrato-κ(2)O,O')nickel(II)] dinitrate, [Ni2(NO3)2(C17H14N6S)2(CH3OH)2](NO3)2, (I), and bis{µ-3-[(pyridin-4-ylmethyl)sulfanyl]-5-(quinolin-2-yl)-4H-1,2,4-triazol-4-amine}bis[(methanol-κO)(nitrato-κ(2)O,O')zinc(II)] dinitrate, [Zn2(NO3)2(C17H14N6S)2(CH3OH)2](NO3)2, (II), by solution reactions with the inorganic salts M(NO3)2 (M = Ni and Zn, respectively) in mixed solvents. In (I), two Ni(II) cations with the same coordination environment are linked by L ligands through Ni-N bonds to form a bimetallic ring. Compound (I) is extended into a two-dimensional network in the crystallographic ac plane via N-H...O, O-H...N and O-H...O hydrogen bonds, and neighbouring two-dimensional planes are parallel and form a three-dimensional structure via π-π stacking. Compound (II) contains two bimetallic rings with the same coordination environment of the Zn(II) cations. The Zn(II) cations are bridged by L ligands through Zn-N bonds to form the bimetallic rings. One type of bimetallic ring constructs a one-dimensional nanotube via O-H...O and N-H...O hydrogen bonds along the crystallographic a direction, and the other constructs zero-dimensional molecular cages via O-H...O and N-H...O hydrogen bonds. They are interlinked into a two-dimensional network in the ac plane through extensive N-H...O hydrogen bonds, and a three-dimensional supramolecular architecture is formed via π-π interactions between the centroids of the benzene rings of the quinoline ring systems.
RESUMEN
Estrogen, via estrogen receptor alpha (ERα), exerts several beneficial effects on metabolism and energy homeostasis by controlling size, enzymatic activity and hormonal content of adipose tissue. The actions of estrogen on sympathetic ganglia, which are key players in the browning process, are less well known. In the present study we show that ERß influences browning of subcutaneous adipose tissue (SAT) via its actions both on sympathetic ganglia and on the SAT itself. A 3-day-treatment with a selective ERß agonist, LY3201, induced browning of SAT in 1-year-old obese WT and ERα-/- female mice. Browning was associated with increased expression of ERß in the nuclei of neurons in the sympathetic ganglia, increase in tyrosine hydroxylase in both nerve terminals in the SAT and sympathetic ganglia neurons and an increase of ß3-adrenoceptor in the SAT. LY3201 had no effect on browning in young female or male mice. In the case of young females browning was already maximal while in males there was very little expression of ERß in the SAT and very little expression of the ß3-adrenoceptor. The increase in both sympathetic tone and responsiveness of adipocytes to catecholamines reveals a novel role for ERß in controlling browning of adipose tissue.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Receptor beta de Estrógeno/agonistas , Obesidad/metabolismo , Grasa Subcutánea Abdominal/metabolismo , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Factores de Edad , Animales , Benzopiranos/farmacología , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Femenino , Expresión Génica , Masculino , Ratones , Ratones Noqueados , Ratones Obesos , Modelos Biológicos , Obesidad/genética , Factores Sexuales , Grasa Subcutánea Abdominal/efectos de los fármacos , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
Three coordination complexes with Cu(I) centres have been prepared using the symmetrical flexible organic ligands 1,3-bis{[5-(quinolin-2-yl)-1,3,4-oxadiazol-2-yl]sulfanyl}propane (L1) and 1,4-bis{[5-(quinolin-2-yl)-1,3,4-oxadiazol-2-yl]sulfanyl}butane (L2). Crystallization of L1 with Cu(SO3CF3)2 and of L2 with Cu(BF4)2 and Cu(ClO4)2 in a CH2Cl2/CH3OH mixed-solvent system at room temperature afforded the coordination complexes catena-poly[[copper(I)-µ-1,3-bis{[5-(quinolin-2-yl)-1,3,4-oxadiazol-2-yl]sulfanyl}propane] methanesulfonate dichloromethane 0.6-solvate], {[Cu(C25H18N6O2S2)](CF3SO3)·0.6CH2Cl2}n, (I), bis(µ-1,4-bis{[5-(quinolin-2-yl)-1,3,4-oxadiazol-2-yl]sulfanyl}butane)dicopper(I) bis(tetrafluoridoborate)-dichloromethane-methanol (1/1.5/1), [Cu2(C26H20N6O2S2)2](BF4)2·1.5CH2Cl2·CH3OH, (II), and bis(µ-1,4-bis{[5-(quinolin-2-yl)-1,3,4-oxadiazol-2-yl]sulfanyl}butane)dicopper(I) bis(perchlorate)-dichloromethane-methanol (1/2/1), [Cu2(C26H20N6O2S2)2](ClO4)2·2CH2Cl2·CH3OH, (III). Under the control of the dumbbell-shaped CF3SO3(-) anion, complex (I) forms a one-dimensional chain and neighbouring chains form a spiral double chain. Under the control of the regular tetrahedron-shaped BF4(-) and ClO4(-) anions, complexes (II) and (III) have been obtained as bimetallic rings, which further interact via π-π interactions to form two-dimensional networks. The anions play a decisive role in determining the arrangement of these discrete molecular complexes in the solid state.