ABSTRACT
Insulin resistance in the vasculature is a characteristic feature of obesity and contributes to the pathogenesis of vascular dysfunction and disease. However, the molecular mechanisms underlying obesity-associated vascular insulin resistance and dysfunction remain poorly understood. We hypothesized that TRAF3IP2 (TRAF3 interacting protein 2), a proinflammatory adaptor molecule known to activate pathological stress pathways and implicated in cardiovascular diseases, plays a causal role in obesity-associated vascular insulin resistance and dysfunction. We tested this hypothesis by employing genetic-manipulation in endothelial cells in vitro, in isolated arteries ex vivo, and diet-induced obesity in a mouse model of TRAF3IP2 ablation in vivo. We show that ectopic expression of TRAF3IP2 blunts insulin signaling in endothelial cells and diminishes endothelium-dependent vasorelaxation in isolated aortic rings. Further, 16 weeks of high fat/high sucrose feeding impaired glucose tolerance, aortic insulin-induced vasorelaxation, and hindlimb postocclusive reactive hyperemia, while increasing blood pressure and arterial stiffness in wild-type male mice. Notably, TRAF3IP2 ablation protected mice from such high fat/high sucrose feeding-induced metabolic and vascular defects. Interestingly, wild-type female mice expressed markedly reduced levels of TRAF3IP2 mRNA independent of diet and were protected against high fat/high sucrose diet-induced vascular dysfunction. These data indicate that TRAF3IP2 plays a causal role in vascular insulin resistance and dysfunction. Specifically, the present findings highlight a sexual dimorphic role of TRAF3IP2 in vascular control and identify it as a promising therapeutic target in vasculometabolic derangements associated with obesity, particularly in males.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Endothelium, Vascular/metabolism , Insulin Resistance/genetics , Insulin/metabolism , Obesity/metabolism , Adaptor Proteins, Signal Transducing/genetics , Animals , Aorta/metabolism , Diet, High-Fat , Disease Models, Animal , Endothelial Cells/metabolism , Humans , Male , Mice , Obesity/genetics , Signal Transduction/physiology , Vasodilation/physiologyABSTRACT
During pregnancy, prolactin (PRL) is a neuro-immuno-cytokine that contributes actively to the crosstalk between the immune and endocrine systems and, thus, to the creation of an immune-privileged milieu. This work aims to analyze the capacity of PRL to modulate the synthesis and secretion of pro-inflammatory markers associated with labor. Studies were conducted using human fetal membranes at term mounted in a model of two independent chambers. The choriodecidual region was stimulated with 500-ng/mL lipopolysaccharide (LPS), and the amnion and choriodecidual region were co-simulated with different concentrations of PRL that can arise during pregnancy: 250, 500, 1000, and 4000ng/mL. Following these co-treatments, the tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and IL-10 levels were measured in both compartments. As expected, treatment with LPS induced all cytokines to increase. Co-stimulation with the highest tested concentration of PRL induced significant decreases in TNF-α in the choriodecidual region and IL-1ß in both regions of the fetal membranes. PRL did not modified the IL-6 and IL-10 secretion profile. These findings, coupled with clinical evidence, suggest that the high level of PRL in the amniotic cavity is involved the mechanism by which the fetal-placental unit regulates the equilibrium between pro- and anti-inflammatory modulators.
Subject(s)
Amnion/immunology , Anti-Inflammatory Agents/metabolism , Decidua/immunology , Prolactin/metabolism , Cells, Cultured , Female , Humans , Immunomodulation , Inflammation Mediators/metabolism , Interleukin-10/metabolism , Lipopolysaccharides/immunology , Neuroimmunomodulation , Organ Culture Techniques , Placental Circulation , PregnancyABSTRACT
Biomarkers are rapidly gaining importance in personalized medicine. Although numerous molecular signatures have been developed over the past decade, there is a lack of overlap and many biomarkers fail to validate in independent patient cohorts and hence are not useful for clinical application. For these reasons, identification of novel and robust biomarkers remains a formidable challenge. We combine targeted proteomics with computational biology to discover robust proteomic signatures for prostate cancer. Quantitative proteomics conducted in expressed prostatic secretions from men with extraprostatic and organ-confined prostate cancers identified 133 differentially expressed proteins. Using synthetic peptides, we evaluate them by targeted proteomics in a 74-patient cohort of expressed prostatic secretions in urine. We quantify a panel of 34 candidates in an independent 207-patient cohort. We apply machine-learning approaches to develop clinical predictive models for prostate cancer diagnosis and prognosis. Our results demonstrate that computationally guided proteomics can discover highly accurate non-invasive biomarkers.
Subject(s)
Biomarkers/urine , Prostatic Neoplasms/urine , Humans , Liquid Biopsy , Male , Mass Spectrometry , Middle Aged , Prostate/pathology , Prostatic Neoplasms/pathology , Proteome , ProteomicsABSTRACT
BACKGROUND: The biochemical bases for hormone dependence in breast cancer have been recognized as an important element in tumor resistance, proliferation and metastasis. On this respect, dexamethasone (Dex) dependent protection against TNF-alpha-mediated cell death in the MCF-7 cell line has been demonstrated to be a useful model for the study of this type of cancer. Recently, cytoplasmic signaling induced by steroid receptors has been described, such as the activation of the PI3K/Akt and NF-kappaB pathways. We evaluated their possible participation in the Dex-dependent protection against TNF-alpha-mediated cell death. RESULTS: Cellular cultures of the MCF-7 cell line were exposed to either, TNF-alpha or TNF-alpha and Dex, and cell viability was evaluated. Next, negative dominants of PI3K and IkappaB-alpha, designed to block the PI3K/Akt and NF-kappaB pathways, respectively, were transfected and selection and evaluation of several clones overexpressing the mutants were examined. Also, correlation with inhibitor of apoptosis proteins (IAPs) expression was examined. Independent inhibition of these two pathways allowed us to test their participation in Dex-dependent protection against TNF-alpha-cytotoxicity in MCF-7 cells. Expression of the PI3K dominant negative mutant did not alter the protection conferred by Dex against TNF-alpha mediated cell death. Contrariwise, clones expressing the IkappaB-alpha dominant negative mutant lost the Dex-conferred protection against TNF-alpha. In these clones degradation of c-IAP was accelerated, while that of XIAP was remained unaffected. CONCLUSION: NF-kappaB, but not PI3K/Akt activation, is required for the Dex protective effect against TNF-alpha-mediated cell death, and correlates with lack of degradation of the anti-apoptotic protein c-IAP1.
Subject(s)
Apoptosis/drug effects , Dexamethasone/pharmacology , NF-kappa B/physiology , Oncogene Protein v-akt/physiology , Tumor Necrosis Factor-alpha/pharmacology , Blotting, Western , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Breast Neoplasms/physiopathology , Cell Cycle Proteins/genetics , Cell Cycle Proteins/physiology , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/genetics , Dual Specificity Phosphatase 1 , Electrophoretic Mobility Shift Assay , Female , Gene Expression Regulation/drug effects , Humans , Immediate-Early Proteins/genetics , Immediate-Early Proteins/physiology , Inhibitor of Apoptosis Proteins/genetics , Inhibitor of Apoptosis Proteins/physiology , NF-kappa B/genetics , Oncogene Protein v-akt/genetics , Phosphoprotein Phosphatases/genetics , Phosphoprotein Phosphatases/physiology , Protein Phosphatase 1 , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/physiology , Protein Tyrosine Phosphatases/genetics , Protein Tyrosine Phosphatases/physiology , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/physiology , Transfection , X-Linked Inhibitor of Apoptosis Protein/genetics , X-Linked Inhibitor of Apoptosis Protein/physiologyABSTRACT
Activity of the magnocellular neurons that synthesize vasopressin and oxytocin in the paraventricular and supraoptic nuclei of the hypothalamus can be modulated by local release of neuromediators within the nuclei. Among the bioactive peptides that may play autocrine or paracrine roles in this system is prolactin (PRL). Paraventricular and supraoptic neurons express PRL mRNA and contain and secrete PRL-like proteins of 23 and 14 kDa. We investigated the localization of PRL receptors in vasopressinergic and oxytocinergic magnocellular neurons using dual-label immunofluorescence. The results demonstrate that both vasopressin- and oxytocin-immunoreactive cells of the paraventricular and supraoptic nuclei contain the PRL receptor. In addition, we investigated the possible regulation of vasopressin secretion by PRL using hypothalamo-neurohypophyseal explants in culture. The results show that PRL and a 16 kDa N-terminal fragment of the hormone that is analogous to the neurohypophyseal 14-kDa PRL fragment stimulate the release of vasopressin. Together, these findings support the hypothesis that vasopressinergic and oxytocinergic neurons of the magnocellular secretory system are regulated directly by various isoforms of PRL via autocrine/paracrine mechanisms.
Subject(s)
Hypothalamo-Hypophyseal System/metabolism , Prolactin/metabolism , Vasopressins/metabolism , Animals , Autocrine Communication/drug effects , Autocrine Communication/physiology , Cells, Cultured , Female , Hypothalamo-Hypophyseal System/cytology , Hypothalamo-Hypophyseal System/drug effects , Hypothalamus, Anterior/cytology , Hypothalamus, Anterior/drug effects , Hypothalamus, Anterior/metabolism , Paracrine Communication/drug effects , Paracrine Communication/physiology , Paraventricular Hypothalamic Nucleus/cytology , Paraventricular Hypothalamic Nucleus/drug effects , Paraventricular Hypothalamic Nucleus/metabolism , Peptide Fragments/pharmacology , Prolactin/pharmacology , Rats , Rats, Wistar , Receptors, Prolactin/metabolismABSTRACT
Se analizaron 1600 expedientes odontopediátricos de niños mexicanos, con el objeto de determinar la relación existentes entre algunos factores biopsicosociales y los malos hábitos bucales, manifestándose una predisposición significativa en los pacientes hijos únicos, niños llamados con algún nombre extranjero y niños con el mismo nombre que su padre o madre, niños con padre ausente, hijos de padres que rehusan a describir las características de conducta del pacientes, e hijos de padres incongruentes en sus descripciones sobre salud (mental y/o física) y su realidad. Asimismo se detectó una correlación significativa con los niños en mal estado de salud presente, especialmente alergias, así como niños con antecedentes de problemas de salud pasada, especialmente las de tipo crónico. Existe valiosa información en los cuestionarios de admisión odontopediátricos, la cual demuestra asociación significativa entre factores biopsicosociales y los malos hábitos bucales, los cuales una vez reconocidos como problema de conducta que afecta los tejidos bucales y parte de los principales problemas de salud bucal, requieren para su prevención y tratamiento, de un abordaje multidisciplinario orientado a atacar directamente la causa del problema
Subject(s)
Humans , Male , Female , Child, Preschool , Adolescent , Habits , Bruxism/epidemiology , Child Behavior/psychology , Nail Biting/psychology , Hypersensitivity/epidemiology , Mouth Breathing/epidemiology , Social Problems , Fingersucking/psychology , Psychotic Disorders/etiologyABSTRACT
Se analizaron 1600 expedientes odontopediátricos con el objeto de determinar la incidencia, prevalencia y distribución de los malos hábitos bucales. Un 56 por ciento de los niños demostraron algún hábito bucal pernicioso, manifestándose una predisposición significativa en los pacientes de sexo femenino. Los hábitos de succión no nutritiva se presentaron con mayor frecuencia en los pacientes del grupo de niñez temprana, mientras que los hábitos de morder se manifestaron predominantemente en preadolescentes y adolescentes. La onicofagia y el bruxismo se presentaron en un 23 por ciento, succión digital y respiración bucal en un 11 por ciento, succión del labio y/o lengua en un 7 por ciento. Un 2 por ciento de los pacientes mostraron aglún otro tipo de mal hábito bucal
