RESUMEN
Retinoic acid receptor-related orphan receptor-alpha (RORα) is a transcription factor from the nuclear receptor family expressed by immune cells and involved in the development of obesity, insulin resistance (IR) and non-alcoholic steatohepatitis (NASH). It was recently reported that mice deficient for RORα in macrophages develop more severe NASH upon high fat diet (HFD) feeding due to altered Kupffer cell function. To better understand the role of RORα in obesity and IR, we independently generated a macrophage RORα-deficient mouse line. We report that RORα deletion in macrophages does not impact on HFD-induced obesity and IR. Surprisingly, we did not confirm an effect on NASH development upon HFD feeding nor in the more severe and obesity-independent choline-deficient, L-amino acid-defined diet model. Our results therefore show that RORα deletion in macrophages does not alter the development of obesity and IR and question its role in NASH.
Asunto(s)
Resistencia a la Insulina , Macrófagos/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Obesidad/metabolismo , Animales , Células Cultivadas , Dieta Alta en Grasa/efectos adversos , Eliminación de Gen , Macrófagos del Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/etiología , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Obesidad/etiologíaRESUMEN
OBJECTIVE: The occurrence of new blood vessel formation in the lungs of asthmatic patients suggests a critical role for airway endothelial cells (ECs) in the disease. IL-33 (Interleukin-33)-a cytokine abundantly expressed in human lung ECs-recently emerged as a key factor in the development of allergic diseases, including asthma. In the present study, we evaluated whether mouse and human ECs exposed to the common Dermatophagoides farinae allergen produce IL-33 and characterized the activated signaling pathways. Approach and Results: Mouse primary lung ECs were exposed in vitro to D farinae extract or rmIL-33 (recombinant murine IL-33). Both D farinae and rmIL-33 induced Il-33 transcription without increasing the IL-33 production and upregulated the expression of its receptor, as well as genes involved in angiogenesis and the regulation of immune responses. In particular, D farinae and rmIL-33 upregulated Fas/Cd95 transcript level, yet without promoting apoptosis. Inhibition of caspases involved in the Fas signaling pathway, increased IL-33 protein level in ECs, suggesting that Fas may decrease IL-33 level through caspase-8-dependent mechanisms. Our data also showed that the NF-κB (nuclear factor-κB), PI3K/Akt, and Wnt/ß-catenin pathways regulate Il-33 transcription in both mouse and human primary ECs. CONCLUSIONS: Herein, we described a new mechanism involved in the control of IL-33 production in lung ECs exposed to allergens.
Asunto(s)
Antígenos Dermatofagoides/farmacología , Células Endoteliales/efectos de los fármacos , Interleucina-33/farmacología , Pulmón/irrigación sanguínea , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor fas/metabolismo , Animales , Caspasa 8/metabolismo , Línea Celular , Células Endoteliales/enzimología , Células Endoteliales/inmunología , Activación Enzimática , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/enzimología , Células Endoteliales de la Vena Umbilical Humana/inmunología , Humanos , Interleucina-33/genética , Interleucina-33/metabolismo , Ratones , Regulación hacia Arriba , Vía de Señalización Wnt , Receptor fas/genéticaRESUMEN
Obesity is a worldwide epidemic that predisposes individuals to cardiometabolic complications, such as type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD), which are all related to inappropriate ectopic lipid deposition. Identification of the pathogenic molecular mechanisms and effective therapeutic approaches are highly needed. The peroxisome proliferator-activated receptors (PPARs) modulate several biological processes that are perturbed in obesity, including inflammation, lipid and glucose metabolism and overall energy homeostasis. Here, we review how PPARs regulate the functions of adipose tissues, such as adipogenesis, lipid storage and adaptive thermogenesis, under healthy and pathological conditions. We also discuss the clinical use and mechanism of PPAR agonists in the treatment of obesity comorbidities such as dyslipidaemia, T2DM and NAFLD. First generation PPAR agonists, primarily those acting on PPARγ, are associated with adverse effects that outweigh their clinical benefits, which led to the discontinuation of their development. An improved understanding of the physiological roles of PPARs might, therefore, enable the development of safe, new PPAR agonists with improved therapeutic potential.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Dislipidemias/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Animales , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/terapia , Dislipidemias/patología , Dislipidemias/terapia , Humanos , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/terapia , Receptores Activados del Proliferador del Peroxisoma/uso terapéuticoRESUMEN
BACKGROUND: Persistent pleural effusions after the Fontan procedure contribute to prolonged hospitalization and increased costs. We report our experience using a modified Wisconsin Fontan protocol to reduce chest tube drainage and hospital length of stay (LOS). METHODS: Single institutional retrospective chart review of 120 consecutive patients (60 before and 60 after initiation of our protocol) undergoing an extracardiac Fontan procedure from January 2004 to February 2007. Protocol influence was assessed by comparing group differences on duration of pleural drainage, requirement for nothing by mouth/total parenteral nutrition, hospital LOS, readmission for pleural effusion, and total hospital costs. RESULTS: Groups were similar in demographic characteristics, single ventricle morphology, preoperative hemodynamic parameters, and operative and immediate postoperative management. Median duration of pleural drainage and hospital LOS was reduced in the post- versus preprotocol groups: 4 days (interquartile range [IQR], 4-5 days) pre versus 6 days (IQR, 5-10 days) (P < .0001) and 6 days (IQR, 5-9 days) versus 8 days (IQR, 6-13 days) (P = .005), respectively. Pleural drainage lasting >1 week was also less common postprotocol: 23 (38%) before versus 7 (12%) after (P = .001). Fewer postprotocol patients required nothing by mouth/total parenteral nutrition to control effusions: 5 pre versus 0 post (P = .06), and fewer readmissions for effusions (14 before vs 7 after [P = .1]). An average total cost savings of 22% and readmissions savings of 29% resulted in nearly $500,000 in institutional savings over the study period. CONCLUSIONS: A modified Fontan protocol resulted in reduced time to chest tube removal, hospital LOS, and chest tube drainage lasting >1 week. There was a strong trend toward avoiding nothing by mouth/total parenteral nutrition to control pleural effusion and lower hospital costs.
Asunto(s)
Procedimiento de Fontan/efectos adversos , Cardiopatías Congénitas/cirugía , Tiempo de Internación , Readmisión del Paciente , Derrame Pleural/terapia , Cuidados Posoperatorios/métodos , Preescolar , Ahorro de Costo , Drenaje/efectos adversos , Femenino , Procedimiento de Fontan/economía , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/economía , Costos de Hospital , Humanos , Tiempo de Internación/economía , Los Angeles , Masculino , Nutrición Parenteral Total , Readmisión del Paciente/economía , Derrame Pleural/diagnóstico , Derrame Pleural/economía , Derrame Pleural/etiología , Cuidados Posoperatorios/efectos adversos , Cuidados Posoperatorios/economía , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: The consumption of antifungal agents increased over the last decade, resulting in the development of resistant organisms and causing a significant pharmaco economic burden. Antifungal drugs are widely used for the treatment of systemic fungal infections and high-risk patients, especially with severe hematological or oncological conditions. Up to date, there are no reliable and systematically reported data on the consumption of antifungal substances on a nationwide level available. The presented study gives an update to the previously published multicenter study investigating antifungal consumption in different settings from five university hospital centers in Germany from 2001 to 2003. METHODS: Consumption data for systemic antifungal drugs were obtained through the hospital pharmacies for 2001-2003 and 2008-2011 regarding the medical and surgical services of five university hospital centers in Germany (A-E). Drug use densities were calculated as yearly RDDs/100 patient days. These calculations were performed for the surgical and medical services, and independently for surgical and medical ICUs, as well as for the hematology-oncology services. RESULTS: We report an increased utilization of systemic antifungal drugs in both study periods. The mean drug use density (mean value of all 5 hospitals) in the medical services increased by 24% between 2001 and 2003. In 2011, this value was 37% above the level from 2001 (12.4 RDD/100 patient days in 2001, 15.4 RDD/100 patient days in 2003, 17.0 RDD/100 patient days in 2011). The 4-year average drug use density (2008-2011) of medical services ranged between 11.6 RDD/100 patient days (hospital E) and 23.8 RDD/100 patient days (hospital A). Drug use densities were in medical intensive care units 29.4 RDD/100 patient days and hematology-oncology services 49.9 RDD/100 patient days. CONCLUSIONS: Despite the variability of the prescribing patterns between the tertiary hospitals, the presented pharmaco-epidemiological data are a cornerstone for the initiation and implementation of effective antifungal stewardship programmes and might serve as important benchmarking information for other hospitals with similar structures and baseline settings.
Asunto(s)
Antifúngicos/uso terapéutico , Farmacorresistencia Fúngica , Revisión de la Utilización de Medicamentos , Micosis/tratamiento farmacológico , Alemania/epidemiología , Hematología , Hospitales Universitarios , Humanos , Unidades de Cuidados Intensivos , Micosis/epidemiología , Servicio de Oncología en Hospital , Servicio de Cirugía en HospitalRESUMEN
Patients with acute lymphoblastic leukaemia (ALL) after cytotoxic chemotherapy or haematopoietic stem cell transplantation (HSCT) are at risk for life-threatening invasive fungal disease (IFD). The aim was to evaluate the characteristics, antifungal therapy and outcome of adult patients with ALL after chemotherapy or HSCT receiving caspofungin empirically in a clinical setting. Retrospective chart reviews were conducted at nine large tertiary care centres in Germany. Adult patients with ALL treated empirically with caspofungin according to the product label between 2006 and 2012 were eligible. Data were extracted as case reports. In total, 25 patients (12 males, 13 females; median age 37 years; 19 with B-ALL, 6 with T-ALL) with 28 treatment episodes because of suspected IFD (18 episodes after chemotherapy, 10 episodes after allogeneic HSCT) were included in the analysis. Empirical caspofungin therapy (median duration: 19 days, range 1-105 days) was given as first-line monotherapy in 20 (71.4%), second-line monotherapy in five (17.9%) and combination therapy in three (10.7%) episodes respectively. Therapy rated successful according to the physician's overall assessment (inflammatory parameters, clinical symptoms): 20 (95%) of 21 evaluable episodes with therapy duration of at least 8 days. Empirical caspofungin appears to be an effective therapeutic option in critically ill adult ALL patients with suspected IFD in clinical practice.
Asunto(s)
Antifúngicos/uso terapéutico , Equinocandinas/uso terapéutico , Micosis/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adulto , Anciano , Caspofungina , Protocolos Clínicos , Femenino , Alemania , Trasplante de Células Madre Hematopoyéticas , Humanos , Lipopéptidos , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Remodeling of quiescent vessels with increases in permeability, vasodilatation, and edema are hallmarks of inflammatory disorders. Factors involved in this type of remodeling represent potential therapeutic targets. OBJECTIVES: We investigated whether the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) ß/δ, a regulator of metabolism, fibrosis, and skin homeostasis, is involved in regulation of this type of remodeling. METHODS: Wild-type and various Pparb/d mutant mice were used to monitor dermal acute vascular hyperpermeability (AVH) and passive systemic anaphylaxis-induced hypothermia and edema. PPARß/δ-dependent kinase activation and remodeling of endothelial cell-cell junctions were addressed by using human endothelial cells. RESULTS: AVH and dilatation of dermal microvessels stimulated by vascular endothelial growth factor A, histamine, and thrombin are severely compromised in PPARß/δ-deficient mice. Selective deletion of the Pparb/d-encoding gene in endothelial cells in vivo similarly limits dermal AVH and vasodilatation, providing evidence that endothelial PPARß/δ is the major player in regulating acute dermal microvessel remodeling. Furthermore, endothelial PPARß/δ regulatory functions are not restricted to the skin vasculature because its deletion in the endothelium, but not in smooth muscle cells, also leads to reduced systemic anaphylaxis, the most severe form of allergic reaction, in which an acute vascular response plays a key role. PPARß/δ-dependent AVH activation likely involves the activation of mitogen-activated protein kinase and Akt pathways and leads to downstream destabilization of endothelial cell-cell junctions. CONCLUSION: These results unveil not only a novel function of PPARß/δ as a direct regulator of acute vessel permeability and dilatation but also provide evidence that antagonizing PPARß/δ represents an important strategy to consider for moderating diseases with altered endothelial integrity, such as acute inflammatory and allergic disorders.
Asunto(s)
Anafilaxia/inmunología , Permeabilidad Capilar/inmunología , Células Endoteliales/inmunología , PPAR delta/inmunología , PPAR-beta/inmunología , Piel/inmunología , Anafilaxia/genética , Anafilaxia/patología , Animales , Permeabilidad Capilar/efectos de los fármacos , Edema/genética , Edema/inmunología , Edema/patología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/patología , Femenino , Regulación de la Expresión Génica , Histamina/farmacología , Hipotermia/genética , Hipotermia/inmunología , Hipotermia/patología , Uniones Intercelulares/efectos de los fármacos , Uniones Intercelulares/inmunología , Uniones Intercelulares/patología , Ratones , Ratones Transgénicos , Proteínas Quinasas Activadas por Mitógenos/genética , Proteínas Quinasas Activadas por Mitógenos/inmunología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/inmunología , Miocitos del Músculo Liso/patología , PPAR delta/deficiencia , PPAR delta/genética , PPAR-beta/deficiencia , PPAR-beta/genética , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/inmunología , Transducción de Señal , Piel/irrigación sanguínea , Piel/efectos de los fármacos , Piel/patología , Trombina/farmacología , Factor A de Crecimiento Endotelial Vascular/farmacologíaRESUMEN
The α-1-acid glycoprotein/orosomucoids (ORMs) are members of the lipocalin protein family. Encoded by 3 polymorphic genes in mouse (2 in man, 1 in rat), ORMs are expressed in hepatocytes and function as acute-phase proteins secreted in plasma under stressful conditions. In addition to their role of nanocarrier, ORMs are involved in several pathophysiological processes such as immunosuppression, cardioprotection, and inflammatory bowel disease. The nuclear bile acid receptor farnesoid X receptor (FXR) regulates bile acid homeostasis and lipid and glucose metabolism and is an important modulator of enterohepatic functions. Here we report that hepatic FXR deletion in mice affects the expression of several members of the lipocalin family, among which ORMs are identified as direct FXR target genes. Indeed, a FXR response element upstream of the mouse Orm1 promoter was identified to which hepatic, but not ileal, FXR can bind and activate ORM expression in vitro and in vivo. However, ORMs are regulated in a species-specific manner because the ORM cluster is regulated by FXR neither in human nor rat cell lines. Consistent with these data, chromatin immunoprecipitation sequencing analysis of the FXR genomic binding sites did not detect any FXR response element in the vicinity of the human or rat ORM gene cluster. Thus, bile acids and their cognate nuclear receptor, FXR, are regulators of ORM expression, with potential implications for the species-specific metabolic and inflammation control by FXR because the expression of the proinflammatory genes in epididymal white adipose tissue was dependent on liver FXR activation.
Asunto(s)
Tejido Adiposo Blanco/metabolismo , Regulación de la Expresión Génica , Hepatocitos/metabolismo , Familia de Multigenes , Orosomucoide/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Elementos de Respuesta , Tejido Adiposo Blanco/inmunología , Animales , Línea Celular , Hepatocitos/inmunología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Especificidad de Órganos , Orosomucoide/biosíntesis , Orosomucoide/genética , Isoformas de Proteínas/biosíntesis , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Ratas , Receptores Citoplasmáticos y Nucleares/genética , Proteínas Recombinantes/metabolismo , Especificidad de la EspecieRESUMEN
STUDY OBJECTIVE: To evaluate the incidence of posaconazole serum levels below 700 µg/L, the rate of breakthrough infections during posaconazole prophylaxis, and factors influencing posaconazole exposure in daily clinical practice. DESIGN: Prospective observational study and review of the literature. SETTING: Hematology and oncology department in a tertiary care academic medical center. PATIENTS: A total of 31 patients with hematologic diseases: 27 received posaconazole prophylaxis and 4 received posaconazole therapy. MEASUREMENTS AND MAIN RESULTS: We analyzed 187 posaconazole serum levels from 31 patients (median of five posaconazole levels per patient; range 1-16). The analyses revealed that 80 of 187 levels (43%) were below 700 µg/L, and 68% of patients were found to have at least one measured level below this threshold. Breakthrough invasive fungal infections categorized as probable or possible infections occurred in 4 of 27 patients (15%) receiving the drug as prophylaxis. A multivariate analysis, accounting for repeated measurements per patient, revealed that age (p=0.02) and mucositis (p=0.04) were associated with significantly reduced posaconazole serum levels. A review of the current literature on posaconazole therapeutic drug monitoring data from real-world studies is presented as an overview table, highlighting the frequency of patients with inadequate posaconazole exposure and heterogeneity of factors influencing posaconazole levels. CONCLUSION: Therapeutic drug monitoring of posaconazole is an important tool of therapy optimization because oral posaconazole suspension shows unreliable absorption rates and exposure.
Asunto(s)
Antifúngicos/farmacocinética , Monitoreo de Drogas/métodos , Micosis/prevención & control , Triazoles/farmacocinética , Centros Médicos Académicos , Administración Oral , Adulto , Factores de Edad , Anciano , Antifúngicos/administración & dosificación , Antifúngicos/uso terapéutico , Femenino , Enfermedades Hematológicas/complicaciones , Enfermedades Hematológicas/tratamiento farmacológico , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Análisis Multivariante , Micosis/epidemiología , Estudios Prospectivos , Factores de Riesgo , Triazoles/administración & dosificación , Triazoles/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND: The outcomes of MM patients vary considerably and depend on a variety of host- and disease-related risks. As yet, a comorbidity risk index in MM patients has neither been standardized nor validated. PATIENTS AND METHODS: We conducted an initial analysis in 127 MM patients and developed the FCI, validating it in an independent cohort of 466 MM patients. The FCI includes patients' Karnofsky Performance Status, renal and lung disease status. We compared the prognostic information of this validated FCI with established comorbidity indices (Hematopoietic Cell Transplantation-Specific Comorbidity Index and Kaplan Feinstein), the International Staging System (ISS), MM therapy, and age. RESULTS: Our validation confirmed that patients with 0, 1, or 2 to 3 FCI risk factors display significantly different overall survival (OS) of not reached, 86, and 39 months, respectively (P < .0001). Via multivariate analysis including the FCI, ISS, therapy, and age, the FCI retained its independent prognostic significance (P < .0015). The combination of the FCI and ISS allowed definition of 3 distinct subgroups with low-risk (FCI 0 and ISS I-II), intermediate-risk (all remaining), and high-risk (FCI 1-3 and ISS III) with OS probabilities at 5-years of 85%, 74%, and 42%, respectively (P < .0001). CONCLUSION: Our validation analysis demonstrated that the FCI remains a reliable comorbidity index, is simpler to generate than other available comorbidity scores, and contributes valuable information to the ISS. Their combination allows the definition of low-, intermediate-, and high-risk patients. These results advocate use of the FCI in future prospective studies and might guide personalized treatment strategies.
Asunto(s)
Mieloma Múltiple/epidemiología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Comorbilidad , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/mortalidad , Mieloma Múltiple/terapia , Estadificación de Neoplasias , Pronóstico , Reproducibilidad de los Resultados , Factores de RiesgoRESUMEN
OBJECTIVE: Dyslipidemia contributes to endothelial dysfunction in type 2 diabetes mellitus. Fenofibrate (FF), a ligand of the peroxisome proliferator-activated receptor-α (PPARα), has beneficial effects on microvascular complications. FF may act on the endothelium by regulating vasoactive factors, including endothelin-1 (ET-1). In vitro, FF decreases ET-1 expression in human microvascular endothelial cells. We investigated the molecular mechanisms involved in the effect of FF treatment on plasma levels of ET-1 in type 2 diabetes mellitus patients. METHODS AND RESULTS: FF impaired the capacity of transforming growth factor-ß to induce ET-1 gene expression. PPARα activation by FF increased expression of the transcriptional repressor Krüppel-like factor 11 and its binding to the ET-1 gene promoter. Knockdown of Krüppel-like factor 11 expression potentiated basal and transforming growth factor-ß-stimulated ET-1 expression, suggesting that Krüppel-like factor 11 downregulates ET-1 expression. FF, in a PPARα-independent manner, and insulin enhanced glycogen synthase kinase-3ß phosphorylation thus reducing glycogen synthase kinase-3 activity that contributes to the FF-mediated reduction of ET-1 gene expression. In type 2 diabetes mellitus, improvement of flow-mediated dilatation of the brachial artery by FF was associated with a decrease in plasma ET-1. CONCLUSIONS: FF decreases ET-1 expression by a PPARα-dependent mechanism, via transcriptional induction of the Krüppel-like factor 11 repressor and by PPARα-independent actions via inhibition of glycogen synthase kinase-3 activity.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dislipidemias/tratamiento farmacológico , Células Endoteliales/efectos de los fármacos , Endotelina-1/metabolismo , Fenofibrato/uso terapéutico , Hipolipemiantes/uso terapéutico , PPAR alfa/agonistas , Proteínas Reguladoras de la Apoptosis , Sitios de Unión , Arteria Braquial/efectos de los fármacos , Arteria Braquial/fisiopatología , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Regulación hacia Abajo , Dislipidemias/sangre , Dislipidemias/metabolismo , Dislipidemias/fisiopatología , Células Endoteliales/metabolismo , Endotelina-1/genética , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Humanos , PPAR alfa/metabolismo , Fosforilación , Regiones Promotoras Genéticas , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Transcripción Genética/efectos de los fármacos , Transfección , Factor de Crecimiento Transformador beta/metabolismo , Vasodilatación/efectos de los fármacosRESUMEN
Dyslipidemia is an important risk factor for cardiovascular disease (CVD) and atherosclerosis. When dyslipidemia coincides with other metabolic disorders such as obesity, hypertension, and glucose intolerance, defined as the metabolic syndrome (MS), individuals present an elevated risk to develop type 2 diabetes (T2D) as well as CVD. Because the MS epidemic represents a growing public health problem worldwide, the development of therapies remains a major challenge. Alterations of bile acid pool regulation in T2D have revealed a link between bile acid and metabolic homeostasis. The bile acid receptors farnesoid X receptor (FXR) and TGR5 both regulate lipid, glucose, and energy metabolism, rendering them potential pharmacological targets for MS therapy. This review discusses the mechanisms of metabolic regulation by FXR and TGR5 and the utility relevance of natural and synthetic modulators of FXR and TGR5 activity, including bile acid sequestrants, in the treatment of the MS.
Asunto(s)
Ácidos y Sales Biliares/metabolismo , Enfermedades Cardiovasculares/tratamiento farmacológico , Dislipidemias/tratamiento farmacológico , Terapia Molecular Dirigida/métodos , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animales , Enfermedades Cardiovasculares/metabolismo , Dislipidemias/metabolismo , Humanos , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/agonistasRESUMEN
Obesity is associated with a significantly increased risk for cancer suggesting that adipose tissue dysfunctions might play a crucial role therein. Macrophages play important roles in adipose tissue as well as in cancers. Here, we studied whether human adipose tissue macrophages (ATM) modulate cancer cell function. Therefore, ATM were isolated and compared with monocyte-derived macrophages (MDM) from the same obese patients. ATM, but not MDM, were found to secrete factors inducing inflammation and lipid accumulation in human T47D and HT-29 cancer cells. Gene expression profile comparison of ATM and MDM revealed overexpression of functional clusters, such as cytokine-cytokine receptor interaction (especially CXC-chemokine) signaling as well as cancer-related pathways, in ATM. Comparison with gene expression profiles of human tumor-associated macrophages showed that ATM, but not MDM resemble tumor-associated macrophages. Indirect co-culture experiments demonstrated that factors secreted by preadipocytes, but not mature adipocytes, confer an ATM-like phenotype to MDM. Finally, the concentrations of ATM-secreted factors related to cancer are elevated in serum of obese subjects. In conclusion, ATM may thus modulate the cancer cell phenotype.
Asunto(s)
Adipocitos/citología , Tejido Adiposo/metabolismo , Regulación Neoplásica de la Expresión Génica , Macrófagos/citología , Neoplasias/metabolismo , Compuestos Azo/farmacología , Línea Celular Tumoral , Quimiocinas/metabolismo , Progresión de la Enfermedad , Humanos , Inmunohistoquímica/métodos , Inflamación , Macrófagos/metabolismo , Obesidad/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , FenotipoRESUMEN
The liver X receptors (LXRs) are nuclear receptors that form permissive heterodimers with retinoid X receptor (RXR) and are important regulators of lipid metabolism in the liver. We have recently shown that RXR agonist-induced hypertriglyceridemia and hepatic steatosis in mice are dependent on LXRs and correlate with an LXR-dependent hepatic induction of lipogenic genes. To further investigate the roles of RXR and LXR in the regulation of hepatic gene expression, we have mapped the ligand-regulated genome-wide binding of these factors in mouse liver. We find that the RXR agonist bexarotene primarily increases the genomic binding of RXR, whereas the LXR agonist T0901317 greatly increases both LXR and RXR binding. Functional annotation of putative direct LXR target genes revealed a significant association with classical LXR-regulated pathways as well as peroxisome proliferator-activated receptor (PPAR) signaling pathways, and subsequent chromatin immunoprecipitation-sequencing (ChIP-seq) mapping of PPARα binding demonstrated binding of PPARα to 71 to 88% of the identified LXR-RXR binding sites. The combination of sequence analysis of shared binding regions and sequential ChIP on selected sites indicate that LXR-RXR and PPARα-RXR bind to degenerate response elements in a mutually exclusive manner. Together, our findings suggest extensive and unexpected cross talk between hepatic LXR and PPARα at the level of binding to shared genomic sites.
Asunto(s)
Hígado/metabolismo , Receptores Nucleares Huérfanos/genética , PPAR alfa/genética , Receptores X Retinoide/genética , Animales , Secuencia de Bases , Sitios de Unión/genética , Cartilla de ADN/genética , Femenino , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Receptores X del Hígado , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores Nucleares Huérfanos/deficiencia , Receptores Nucleares Huérfanos/metabolismo , PPAR alfa/agonistas , PPAR alfa/metabolismo , Receptor Cross-Talk , Receptores X Retinoide/metabolismoRESUMEN
BACKGROUND: The UNDP/WHO/World Bank/Special Programme of Research, Development and Research Training in Human Reproduction (Geneva) set up a study to determine whether it is feasible for women to monitor their ovarian activity reliably by home testing. Daily self-monitoring of urinary hormone metabolites for menstrual cycle assessment was evaluated by comparison of results obtained with the Home Ovarian Monitor by untrained users both at home and in study centres. METHODS: Women collected daily data for urinary estrone glucuronide (E1G) and pregnanediol glucuronide (PdG) for two cycles, then the procedure was repeated in the women's local centre (in Chile, Australia or New Zealand) giving a total of 113 duplicate cycles. The tests were performed without the benefit of replicates or quality controls. The home and centre cycles were normalized and compared to identify assay errors, and the resulting home and centre menstrual cycle profiles were averaged. RESULTS: Reliable mean cycle profiles were obtained with the home and centre excretion rates agreeing to within 36 ± 21 nmol/24 h for E1G and 0.77 ± 0.28 µmol/24 h for baseline PdG values (1-5 µmol/24 h). The cycles had a mean length of 28.1 ± 3.1 days (n = 112; 5th and 95th percentiles: 24 and 35 days, respectively), a mean follicular phase of 14.8 ± 3.1 days (n = 107; 5th and 95th percentiles: 11 and 21 days) and a mean luteal phase length of 13.3 ± 1.5 days (n = 106; 5th and 95th percentiles: 11 and 17 days), calculated from the day of the LH peak. CONCLUSIONS: The study confirmed that the Ovarian Monitor pre-coated assay tubes worked well even in the hands of lay users, without standard curves, quality controls or replicates. Point-of-care monitoring to give reliable fertility data is feasible.
Asunto(s)
Estrona/análogos & derivados , Glucurónidos/orina , Ovario/fisiología , Detección de la Ovulación/instrumentación , Ovulación/orina , Pregnanodiol/análogos & derivados , Autocuidado , Adulto , Australia , Chile , Estrona/orina , Estudios de Factibilidad , Femenino , Humanos , Ensayo de Materiales , Ciclo Menstrual , Nueva Zelanda , Sistemas de Atención de Punto , Pregnanodiol/orina , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND & AIMS: Glucagon-like peptide (GLP)-1, an intestinal incretin produced by L cells through proglucagon processing, is secreted after nutrient ingestion and acts on endocrine pancreas beta cells to enhance insulin secretion. Peroxisome proliferator-activated receptor (PPAR) ß/δ is a nuclear receptor that improves glucose homeostasis and pancreas islet function in diabetic animal models. Here, we investigated whether PPARß/δ activation regulates L cell GLP-1 production. METHODS: Proglucagon regulation and GLP-1 release were evaluated in murine GLUTag and human NCI-H716 L cells and in vivo using wild-type, PPARß/δ-null, and ob/ob C57Bl/6 mice treated with the PPARß/δ synthetic agonists GW501516 or GW0742. RESULTS: PPARß/δ activation increased proglucagon expression and enhanced glucose- and bile acid-induced GLP-1 release by intestinal L cells in vitro and ex vivo in human jejunum. In vivo treatment with GW0742 increased proglucagon messenger RNA levels in the small intestine in wild-type but not in PPARß/δ-deficient mice. Treatment of wild-type and ob/ob mice with GW501516 enhanced the increase in plasma GLP-1 level after an oral glucose load and improved glucose tolerance. Concomitantly, proglucagon and GLP-1 receptor messenger RNA levels increased in the small intestine and pancreas, respectively. Finally, PPARß/δ agonists activate the proglucagon gene transcription by interfering with the ß-catenin/TCF-4 pathway. CONCLUSIONS: Our data show that PPARß/δ activation potentiates GLP-1 production by the small intestine. Pharmacologic targeting of PPARß/δ is a promising approach in the treatment of patients with type 2 diabetes mellitus, especially in combination with dipeptidyl peptidase IV inhibitors.
Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Células Enteroendocrinas/metabolismo , Regulación de la Expresión Génica , Péptido 1 Similar al Glucagón/biosíntesis , PPAR-beta/metabolismo , ARN Mensajero/genética , Animales , Glucemia/metabolismo , Western Blotting , Células Cultivadas , Diabetes Mellitus Experimental/patología , Modelos Animales de Enfermedad , Células Enteroendocrinas/patología , Péptido 1 Similar al Glucagón/genética , Humanos , Masculino , Ratones , Reacción en Cadena de la Polimerasa , ARN Mensajero/biosíntesis , RatasRESUMEN
OBJECTIVE: Bexarotene (Targretin) is a clinically used antitumoral agent which exerts its action through binding to and activation of the retinoid-X-receptor (RXR). The most frequent side-effect of bexarotene administration is an increase in plasma triglycerides, an independent risk factor of cardiovascular disease. The molecular mechanism behind this hypertriglyceridemia remains poorly understood. METHODS AND RESULTS: Using wild-type and LXR alpha/beta-deficient mice, we show here that bexarotene induces hypertriglyceridemia and activates hepatic LXR-target genes of lipogenesis in an LXR-dependent manner, hence exerting a permissive effect on RXR/LXR heterodimers. Interestingly, RNA analysis and Chromatin Immunoprecipitation assays performed in the liver reveal that the in vivo permissive effect of bexarotene on the RXR/LXR heterodimer is restricted to lipogenic genes without modulation of genes controlling cholesterol homeostasis. CONCLUSIONS: These findings demonstrate that the hypertriglyceridemic action of bexarotene occurs via the RXR/LXR heterodimer and show that RXR heterodimers can act with a selective permissivity on target genes of specific metabolic pathways in the liver.
Asunto(s)
Colesterol/metabolismo , Proteínas de Unión al ADN/fisiología , Hígado/metabolismo , Receptores Citoplasmáticos y Nucleares/fisiología , Receptores X Retinoide/fisiología , Tetrahidronaftalenos/farmacología , Triglicéridos/metabolismo , Animales , Bexaroteno , Proteínas de Unión al ADN/química , Dimerización , Femenino , Homeostasis , Lipogénesis , Receptores X del Hígado , Ratones , Ratones Endogámicos C57BL , Receptores Nucleares Huérfanos , Receptores Citoplasmáticos y Nucleares/química , Receptores X Retinoide/químicaRESUMEN
Patients with type-2 diabetes mellitus (T2DM) are considered to be at particularly high risk for cardiovascular disease. Over the last decade, the members of the peroxisome proliferator-activated receptor (PPAR) subfamily of nuclear receptors have emerged as valuable pharmacological targets whose activation can normalize metabolic dysfunctions and reduce some cardiovascular risk factors associated with T2DM. PPARalpha agonists, such as the fibrates, can correct dyslipidemia. PPARgamma agonists, such as the thiazolidinediones, act as insulin sensitizers and improve insulin resistance in patients with T2DM. Because of restricted potency and certain side-effects of PPAR agonists, as well as the increasingly epidemic incidence of T2DM, there is a real need for the development of selective PPAR agonists with improved clinical efficacy. This chapter focuses on the PPAR agonists currently used in the clinic, as well as on the discovery and development of the next generation of PPAR agonists.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Receptores Activados del Proliferador del Peroxisoma/agonistas , Animales , Glucemia/metabolismo , Enfermedades Cardiovasculares/prevención & control , Homeostasis/efectos de los fármacos , Humanos , Insulina/fisiología , Resistencia a la Insulina/fisiología , Metabolismo de los Lípidos/efectos de los fármacos , Lipoproteínas/metabolismo , PPAR alfa/agonistas , PPAR alfa/fisiología , PPAR delta/agonistas , PPAR delta/fisiología , PPAR gamma/agonistas , PPAR gamma/fisiología , Tiazolidinas/farmacologíaRESUMEN
The sex steroid progesterone is essential for the proliferation and differentiation of the mammary gland epithelium during pregnancy. In relation to this, in vitro studies using breast carcinoma T47D cells have demonstrated a biphasic progesterone response, consisting of an initial proliferative burst followed by a sustained growth arrest. However, the transcriptional factors acting with the progesterone receptor (PR) to mediate the progesterone effects on mammary cell growth and differentiation remain to be determined. Recently, it has been demonstrated that the transcriptional regulating protein of 132 kDa (TReP-132), initially identified as a regulator of steroidogenesis, is also a cell growth suppressor. Similar to progesterone-bound PR, TReP-132 acts by inducing the gene expression of the G1 cyclin-dependent kinase inhibitors p21WAF1/Cip1 (p21) and p27Kip1 (p27). The putative interaction between TReP-132 and progesterone pathways in mammary cells was therefore analyzed in the present study. Our results show that TReP-132 interacts in vitro and in T47D cells with progesterone-activated PR. TReP-132 synergizes with progesterone-bound PR to trans activate the p21 and p27 gene promoters at proximal Sp1-binding sites. Moreover, TReP-132 overexpression and knockdown, respectively, increased or prevented the induction of p21 and p27 gene expression by progesterone. As a consequence, TReP-132 knockdown also resulted in the loss of the inhibitory effects of progesterone on pRB phosphorylation, G1/S cell cycle progression, and cell proliferation. Furthermore, the knockdown of TReP-132 expression also prevented the induction of both early and terminal markers of breast cell differentiation which had been previously identified as progesterone target genes. As well, the progesterone-induced accumulation of lipid vacuoles was inhibited in the TReP-132-depleted cells. Finally, TReP-132 gene expression levels increased following progesterone treatment, indicating the existence of a positive auto-regulatory loop between PR and TReP-132. Taken together, these data identify TReP-132 as a coactivator of PR mediating the growth-inhibitory and differentiation effects of progesterone on breast cancer cells.
Asunto(s)
Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Diferenciación Celular/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Progesterona/farmacología , Receptores de Progesterona/metabolismo , Factores de Transcripción/metabolismo , Sitios de Unión , Neoplasias de la Mama/genética , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Proteínas de Unión al ADN/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Regiones Promotoras Genéticas/genética , ARN Interferente Pequeño/genética , Receptores de Progesterona/genética , Factores de Transcripción/genéticaRESUMEN
In humans, fibrates are used to treat dyslipidemia, because these drugs lower plasma triglycerides and raise HDL cholesterol. Treatment with fibrates lowers plasma phospholipid transfer protein (PLTP) activity in humans, but increases PLTP activity in mice, without a consistent effect on HDL-cholesterol concentration. Earlier, we found that PLTP overexpression in transgenic mice results in decreased plasma HDL levels and increased diet-induced atherosclerosis. So it seems that the interplay between fibrates, PLTP and HDL is different in mice and man, which may be important for atherosclerosis development. In the present study, we measured the effects of fibrates on PLTP expression in cultured human hepatocytes and effects of fibrate treatment on human PLTP expression, plasma PLTP activity and HDL levels in human PLTP transgenic mice. Fibrate treatment did not influence PLTP mRNA levels in human hepatocytes. Hepatic human PLTP mRNA levels and PLTP activity were both moderately elevated by fenofibrate treatment in human PLTP transgenic mice. In wild-type mice, however, feeding fenofibrate resulted in a strong induction of PLTP mRNA in the liver and a more than 4-fold increase of plasma PLTP activity. Plasma triglycerides were reduced in all mice by 48% or more by fenofibrate treatment. HDL-cholesterol concentrations were substantially increased by fenofibrate in PLTP overexpressing mice (+72%), but unaffected in wild-type mice. We conclude that fenofibrate treatment reverses the HDL-lowering effect of PLTP overexpression in human PLTP transgenic mice.