RESUMEN
[Figure: see text].
Asunto(s)
Aorta/enzimología , Enfermedades de la Aorta/prevención & control , Aterosclerosis/prevención & control , Técnicas de Inactivación de Genes , Hígado/enzimología , Placa Aterosclerótica , Prolil Hidroxilasas/genética , Animales , Aorta/patología , Enfermedades de la Aorta/enzimología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/patología , Aterosclerosis/enzimología , Aterosclerosis/genética , Aterosclerosis/patología , Autoanticuerpos/sangre , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Lipoproteína Lipasa/metabolismo , Lipoproteínas LDL/inmunología , Lipoproteínas LDL/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de LDL/genética , Receptores de LDL/metabolismo , Transcriptoma , Triglicéridos/sangreRESUMEN
OBJECTIVE: Small-molecule hypoxia-inducible factor prolyl 4-hydroxylase (HIF-P4H) inhibitors are being explored in clinical studies for the treatment of anemia. HIF-P4H-2 (also known as PHD2 or EglN1) inhibition improves glucose and lipid metabolism and protects against obesity and metabolic dysfunction. We studied here whether HIF-P4H-2 inhibition could also protect against atherosclerosis. APPROACH AND RESULTS: Atherosclerosis development was studied in low-density lipoprotein (LDL) receptor-deficient mice treated with an oral HIF-P4H inhibitor, FG-4497, and in HIF-P4H-2-hypomorphic/C699Y-LDL receptor-mutant mice, all mice being fed a high-fat diet. FG-4497 administration to LDL receptor-deficient mice reduced the area of atherosclerotic plaques by ≈50% when compared with vehicle-treated controls and also reduced their weight gain, insulin resistance, liver and white adipose tissue (WAT) weights, adipocyte size, number of inflammation-associated WAT macrophage aggregates and the high-fat diet-induced increases in serum cholesterol levels. The levels of atherosclerosis-protecting circulating autoantibodies against copper-oxidized LDL were increased. The decrease in atherosclerotic plaque areas correlated with the reductions in weight, serum cholesterol levels, and WAT macrophage aggregates and the autoantibody increase. FG-4497 treatment stabilized HIF-1α and HIF-2α and altered the expression of glucose and lipid metabolism and inflammation-associated genes in liver and WAT. The HIF-P4H-2-hypomorphic/C699Y-LDL receptor-mutant mice likewise had a ≈50% reduction in atherosclerotic plaque areas, reduced WAT macrophage aggregate numbers, and increased autoantibodies against oxidized LDL, but did not have reduced serum cholesterol levels. CONCLUSIONS: HIF-P4H-2 inhibition may be a novel strategy for protecting against the development of atherosclerosis. The mechanisms involve beneficial modulation of the serum lipid profile and innate immune system and reduced inflammation.
Asunto(s)
Aorta/efectos de los fármacos , Enfermedades de la Aorta/prevención & control , Aterosclerosis/prevención & control , Inhibidores Enzimáticos/farmacología , Prolina Dioxigenasas del Factor Inducible por Hipoxia/antagonistas & inhibidores , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/enzimología , Adiposidad/efectos de los fármacos , Animales , Aorta/enzimología , Aorta/inmunología , Aorta/patología , Enfermedades de la Aorta/sangre , Enfermedades de la Aorta/enzimología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/inmunología , Enfermedades de la Aorta/patología , Aterosclerosis/sangre , Aterosclerosis/enzimología , Aterosclerosis/genética , Aterosclerosis/inmunología , Aterosclerosis/patología , Autoanticuerpos/sangre , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Células Cultivadas , Colesterol/sangre , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Prolina Dioxigenasas del Factor Inducible por Hipoxia/genética , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Inmunidad Innata/efectos de los fármacos , Mediadores de Inflamación/sangre , Resistencia a la Insulina , Lipoproteínas LDL/inmunología , Lipoproteínas LDL/metabolismo , Hígado/efectos de los fármacos , Hígado/enzimología , Macrófagos/efectos de los fármacos , Macrófagos/enzimología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Placa Aterosclerótica , Estabilidad Proteica , Receptores de LDL/deficiencia , Receptores de LDL/genética , Factores de Tiempo , Aumento de Peso/efectos de los fármacosRESUMEN
Stretch marks (striae distensae) are common dermal scarring associated with weight gain, overweight, and pregnancy. Scarring is caused by overstretching of the skin's dermis with permanent structural alteration of the collagen network fibers. Some individuals have naturally weak connective tissue and may develop major stretch marks without being overweight. Stretch marks can develop during puberty and after physical exercise with rapid muscle growth. Cortisone treatment and anabolic steroids often cause stretch marks. Stretch marks are of major cosmetic concern to many. They are red and swollen in the early sate and white and irregular in texture in the later stage. Many men and women suffer from poor self-esteem caused by stretch marks. Medical tattooing of stretch marks, also known as microneedling, can correct the skin pigmentation color in the normal direction, but not the actual textural change. However, abnormal texture may be modified by microneedling, by nonablative laser treatment, or by microdermabrasion. Treatments can also be combined, e.g., initial use of a method to flatten the skin, followed by tattooing to correct the color. Treatment options and strategies are reviewed.
Asunto(s)
Estrías de Distensión , Tatuaje , Masculino , Femenino , Humanos , Estrías de Distensión/etiología , Estrías de Distensión/terapia , Estrías de Distensión/patología , Tatuaje/efectos adversos , Cicatriz/complicaciones , Cicatriz/patología , Sobrepeso/complicaciones , Sobrepeso/patología , Piel/patología , Resultado del TratamientoRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
Hypoxia of residence at high altitude (>2500 m) decreases birth weight. Lower birth weight associates with infant mortality and morbidity and increased susceptibility to later-in-life cardiovascular and metabolic diseases. We sought to determine the effects of hypoxia on maternal glucose and lipid metabolism and their contributions to fetal weight. C57BL6/NCrl mice, housed throughout gestation in normobaric hypoxia (15% oxygen) or normoxia, were studied at mid (E9.5) or late gestation (E17.5). Fetal weight at E17.5 was 7% lower under hypoxia than normoxia. The hypoxic compared with normoxic dams had ~20% less gonadal white adipose tissue at mid and late gestation. The hypoxic dams had better glucose tolerance and insulin sensitivity compared with normoxic dams and failed to develop insulin resistance in late gestation. They also had increased glucagon levels. Glucose uptake to most maternal tissues was ~2-fold greater in the hypoxic than normoxic dams. The alterations in maternal metabolism in hypoxia were associated with upregulation of hypoxia-inducible factor (HIF) target genes that serve, in turn, to increase glycolytic metabolism. We conclude that environmental hypoxia alters maternal metabolism by upregulating the HIF-pathway, and suggest that interventions that antagonize such changes in metabolism in high-altitude pregnancy may be helpful for preserving fetal growth.
Asunto(s)
Tejido Adiposo Blanco/metabolismo , Desarrollo Fetal/genética , Glucosa/metabolismo , Glucólisis/genética , Hipoxia/metabolismo , Metabolismo de los Lípidos/genética , Animales , Peso al Nacer , Embrión de Mamíferos , Femenino , Feto , Regulación de la Expresión Génica , Edad Gestacional , Glucagón/metabolismo , Prueba de Tolerancia a la Glucosa , Hipoxia/genética , Hipoxia/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ratones , Ratones Endogámicos C57BL , Ovario/metabolismo , EmbarazoRESUMEN
Erythrocytosis is driven mainly by erythropoietin, which is regulated by hypoxia-inducible factor (HIF). Mutations in HIF prolyl 4-hydroxylase 2 (HIF-P4H-2) (PHD2/EGLN1), the major downregulator of HIFα subunits, are found in familiar erythrocytosis, and large-spectrum conditional inactivation of HIF-P4H-2 in mice leads to severe erythrocytosis. Although bone marrow is the primary site for erythropoiesis, spleen remains capable of extramedullary erythropoiesis. We studied HIF-P4H-2-deficient (Hif-p4h-2gt/gt) mice, which show slightly induced erythropoiesis upon aging despite nonincreased erythropoietin levels, and identified spleen as the site of extramedullary erythropoiesis. Splenic hematopoietic stem cells (HSCs) of these mice exhibited increased erythroid burst-forming unit (BFU-E) growth, and the mice were protected against anemia. HIF-1α and HIF-2α were stabilized in the spleens, while the Notch ligand genes Jag1, Jag2, and Dll1 and target Hes1 became downregulated upon aging HIF-2α dependently. Inhibition of Notch signaling in wild-type spleen HSCs phenocopied the increased BFU-E growth. HIFα stabilization can thus mediate non-erythropoietin-driven splenic erythropoiesis via altered Notch signaling.
Asunto(s)
Regulación hacia Abajo , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Policitemia/metabolismo , Policitemia/patología , Receptores Notch/metabolismo , Envejecimiento/patología , Anemia/complicaciones , Anemia/patología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Médula Ósea/patología , Recuento de Células , Ensayo de Unidades Formadoras de Colonias , Células Precursoras Eritroides/metabolismo , Hiperplasia , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inflamación/complicaciones , Inflamación/patología , Ligandos , Masculino , Megacariocitos/patología , Ratones , Modelos Biológicos , Estabilidad Proteica , Transducción de Señal , Bazo/patologíaRESUMEN
Fresh vegetables may be contaminated by pathogens in different ways after harvest. Pathogenic microorganisms associated with fresh vegetables can cause severe outbreaks of foodborne disease. We discuss here the results of microbiological analysis of carrot samples, as well as of washing, processing, and wastewater samples. Washed, unpeeled carrots generally contained the highest aerobic plate counts (mean, 5.5 log CFU/g). Escherichia coli was not detected in any carrot or water sample examined. The amounts of coliform bacteria and enterobacteria were higher in carrot samples taken from the first steps in the processing line than in samples taken in later phases of the process. Yersinia pseudotuberculosis was not detected in any of the samples by the cultivation method; however, nonpathogenic Yersinia enterocolitica was detected from most carrot samples and almost all washing water and wastewater samples but only from 2 of 10 process water samples. Using a more-sensitive real-time PCR method, pathogenic Y. enterocolitica was found from several carrot samples, and when these positive samples were cultivated, no pathogenic Y. enterocolitica strains were detected.
Asunto(s)
Daucus carota/microbiología , Contaminación de Alimentos/análisis , Manipulación de Alimentos/métodos , Microbiología del Agua , Yersinia enterocolitica/aislamiento & purificación , Escherichia coli/aislamiento & purificación , Manipulación de Alimentos/normas , Microbiología de Alimentos , Inocuidad de los AlimentosRESUMEN
During recent years increasing effort has been made to modify surface properties with easy-to-clean or self-cleaning characteristics, and concomitantly there is a need to be able to quantify cleanability. Methodology is a complex issue, including aspects of selection and characterization of the surface materials, the soiling materials (contaminants), soiling and cleaning methods, and the detection methods. Different biological, chemical, physical and visual methods have been included in studies of surface cleanability. One challenge has been to obtain quantitative information about soiling. The radiochemical methods, gamma spectrometry (NaI(Tl)-crystal) and liquid scintillation counting, have been shown to be suitable for evaluating cleanability of different surface materials and different soiling material types, providing quantitative information about the amount of soiling material both on and beneath the surface. Due to the different labelled soiling components, the interaction of the surface with different soiling material types can be evaluated. Radiochemical methods have unique benefits particularly for examining porous materials and surfaces. However, they are suitable only for highly controlled studies because of the hazards. Different features and details of radiochemical methods are discussed with the view to aid planning of future cleanability studies.