Oxidative, Reductive, and Nitrosative Stress Effects on Epigenetics and on Posttranslational Modification of Enzymes in Cardiometabolic Diseases.

Oxidative (OS), reductive (RS), and nitrosative (NSS) stresses produce carbonylation, glycation, glutathionylation, sulfhydration, nitration, and nitrosylation reactions. OS, RS, and NSS are interrelated since RS results from an overactivation of antioxidant systems and NSS is the result of the overactivation of the oxidation of nitric oxide (NO). Here, we discuss the general characteristics of the three types of stress and the way by which the reactions they induce (a) damage the DNA structure causing strand breaks or inducing the formation of 8-oxo-d guanosine; (b) modify histones; (c) modify the activities of the enzymes that determine the establishment of epigenetic cues such as DNA methyl transferases, histone methyl transferases, acetyltransferases, and deacetylases; (d) alter DNA reparation enzymes by posttranslational mechanisms; and (e) regulate the activities of intracellular enzymes participating in metabolic reactions and in signaling pathways through posttranslational modifications. Furthermore, the three types of stress may establish new epigenetic marks through these reactions. The development of cardiometabolic disorders in adult life may be programed since early stages of development by epigenetic cues which may be established or modified by OS, RS, and NSS. Therefore, the three types of stress participate importantly in mediating the impact of the early life environment on later health and heritability. Here, we discuss their impact on cardiometabolic diseases. The epigenetic modifications induced by these stresses depend on union and release of chemical residues on a DNA sequence and/or on amino acid residues in proteins, and therefore, they are reversible and potentially treatable.

Prolactin prevents mitochondrial dysfunction induced by glutamate excitotoxicity in hippocampal neurons.

Prolactin (PRL) is a pleiotropic hormone secreted by several cells and tissues in the body, such as mammary glands, T-lymphocytes, hypothalamus, among others. This hormone possess neuroprotective properties against glutamate-excitotoxicity through the activation of NF-kB, suggesting it could exert an antioxidant action. However, the role of PRL on the antioxidant defense during glutamate-induced excitotoxicity is not clear to date. Therefore, in the present study, we have evaluated the effect of PRL on SOD activity and protein content of both of its isoforms (Mn2+-SOD and Cu2+/Zn2+-SOD), as well as, its action on mitochondrial activity in primary culture of hippocampal neurons of rats. Additionally, we have evaluated the possible antioxidant effect of PRL through the determination of lipid peroxidation products (LPO), measured as malondialdehyde (MDA). Results show that PRL enhances the activity and the protein content of Mn2+-SOD and Cu2+/Zn2+-SOD in neurons exposed to glutamate-induced excitotoxicity. Moreover, our results demonstrate that PRL prevents mitochondrial dysfunction induced by glutamate and significantly decreases the levels of LPO products. To our knowledge, this is the first time that a potential antioxidant effect of PRL has been described in hippocampal neurons exposed to glutamate excitotoxicity, opening questions of its potentiality for therapeutics.

Effects of topical capsaicin combined with moderate exercise on insulin resistance, body weight and oxidative stress in hypoestrogenic obese rats.

BACKGROUND: Hypoestrogenic (HE) women are one of the most vulnerable groups for the development of obesity and its complications. Capsaicin and exercise have demonstrated to reduce body weight and to improve insulin sensitivity in different animal models, but it is unknown whether their combination could be useful in HE obese females. METHODS: We investigated whether topical capsaicin, exercise or their combination had better therapeutic effects in an obesity-hypoestrogenism model. Ovariectomized Wistar rats were given a 30% sucrose solution (HE-Obese (HEOb)) or purified water (HE) during 28 weeks ad libitum; four experimental groups per each condition. After shaving the abdominal skin, cold cream vehicle was applied to the Sedentary groups (Sed) and capsaicin cream 0.075% (0.6 mg kg-1 per day) to the Capsaicin groups (Cap). Exercise (Ex) groups ran on a treadmill every day for 20 min at speeds from 9 to 18 m per min increased every 10 days; combination groups (Cap+Ex) were given topical capsaicin 90 min before exercise. The treatments were performed for 6 weeks, and caloric intake and body weight were monitored. At the end of the experimental protocol, glucose tolerance tests were performed, the animals were killed by decapitation; blood and organs were obtained to perform oxidative profile, histology, biochemical analyses and Western blot. RESULTS: In HEOb rats, the combined therapy reduced caloric intake, body weight and abdominal fat in a higher proportion than the individual treatments; it also decreased insulin resistance (IR), oxidative stress and pancreatic islet size. It was the only treatment that significantly increased p-AMPK levels in the soleus muscle. In HE rats, topical capsaicin was the only treatment that reduced glucose intolerance and improved the oxidative profile in a higher proportion than the combined therapy or Ex alone. CONCLUSIONS: Capsaicin per se or its combination with moderate exercise could be a useful therapy against complications linked to obesity-IR in HE females.

17ß Estradiol Modulates Perfusion Pressure and Expression of 5-LOX and CYP450 4A in the Isolated Kidney of Metabolic Syndrome Female Rats.

Prevalence of metabolic syndrome and progression of nephropathy depend on sex. We examined a protective effect of estradiol against nephropathy in metabolic syndrome through the modulation of the arachidonic acid metabolism by activating the 5-lipoxygenase and cytochrome p450 4A pathways. 28 female Wistar rats were divided into four groups of seven animals each: control, intact metabolic syndrome, ovariectomized metabolic syndrome, and metabolic syndrome ovariectomized plus estradiol. Blood pressure, body weight, body fat, triglycerides, insulin, HOMA-index, albuminuria, and TNF-α were increased in ovariectomized metabolic syndrome rats (p < 0.001). The perfusion pressure in isolated kidneys of ovariectomized metabolic syndrome rats in presence of 4 µg of arachidonic acid was increased. The inhibitors of the arachidonic acid metabolism Baicalein, Miconazole, and Indomethacin in these rats decreased the perfusion pressure by 57.62%, 99.83%, and 108.5%, respectively and they decreased creatinine clearance and the arachidonic acid percentage. Phospholipase A2 expression in the kidney of ovariectomized metabolic syndrome rats was not modified. 5-lipoxygenase was increased in metabolic syndrome ovariectomized rats while cytochrome p450 4A was decreased. In conclusion, the loss of estradiol increases renal damage while the treatment with estradiol benefits renal function by modulating arachidonic acid metabolism through the 5-lipoxygenase and cytochrome p450 4A pathways.

Medicinal agents and metabolic syndrome.

The definition of the Metabolic Syndrome (MS) has encountered difficulty in reaching a universal consensus although there exists an agreement of its main pathologies which are hypertension, obesity, dyslipidemia, insulin resistance, inflammation and renal damage. The prevalent opinion is that three of those alterations may define the syndrome. The incidence of the MS has increased globally, particularly in the last few years, to the point of being regarded as an epidemic. The treatment of the MS can be approached from different angles, since it may be a multifaceted health problem. A healthy lifestyle, which means the practice of regular exercise is suggested to MS patients. Increasing physical activity has anti-inflammatory effects since there is an inverse association of physical activity and inflammatory biomarker concentrations. An adequate diet is recommended, such as the Mediterranean, which contains fish, tomatoes, garlic, red peppers, olive oil and includes red wine, that is, antioxidants and non-saturated oils. There are also the traditional herbal preparations, used in the alternative medicine. Several therapeutic tools can be used; the most common are the pharmaceutical products to deal with obesity, hypertension, dyslipidemias, diabetes and inflammation. In addition several pharmacological therapies such as non steroidal anti-inflammatory drugs are recommended. Recently new mechanisms of action of statins, fibrates, metformin and thiazolidinediones have demonstrated their anti-inflammatory effect and potential use to treat MS.

Sex steroid hormones, cardiovascular diseases and the metabolic syndrome.

The metabolic syndrome (MS) has become the new epidemic of this century. Although its associated pathologies may vary, the most common are hypertension, central obesity, dyslipidemia, low High Density Lipoproteins (HDL), high Low Density Lipoproteins (LDL), and type-2 diabetes. Several others can be present, such as hypertriglyceridemia, cardiopathies, atherosclerosis, altered levels of sex hormones, hypogonadism in men and nephropathy. Several factors such as gender, age, race, lifestyle and diet may contribute to modify its prevalence: men develop cardiovascular diseases at an earlier age than pre-menopausal women, who seem to be protected by the antioxidant properties of estrogens. The present review offers information, mostly from 2008 to the present, as well as our own work on a rat model of MS, which was developed by the administration of sucrose in drinking water. Sex steroid hormones play an important role in the appearance and development of the MS and of cardiovascular diseases. Variations in the levels of sex hormones, whether normal or pathological, may have significant influence in the onset of several diseases, metabolic syndrome components included, as well as in the behavior of tissues and organs. These are just some of the non-reproductive actions of sex hormones.

Sex hormones, metabolic syndrome and kidney.

In the metabolic syndrome (MS), a condition that associates three or more pathologies such as hypertension, central obesity, type II diabetes, insulin resistance and dyslipidemias, the kidneys are severely affected. The pathological alterations in the kidneys, associated with MS, may be modified by sex hormone levels. In general, estrogens are a protection against the development of cardiovascular and renal diseases in humans and experimental models, but androgens may have an opposite effect. Among the metabolic systems that can be modulated by sex hormones in the kidney, the more important are: renin-angiotensin-aldosterone system, arachidonic acid metabolism, nitric oxide system and renal extra-cellular matrix proteins. These are metabolic pathways normally associated, in order to maintain the most efficient functioning of renal hemodynamics. There is a close interrelationship between sex hormones and some pathways involved in the metabolic syndrome; also pathways can modulate each other. The circulating concentrations of hormones may determine the degree of overall pathological alterations in the syndrome.

Medicinal agents in the metabolic syndrome.

The metabolic syndrome (MS) has become a worldwide health problem. It is difficult for patients to follow a diet/exercise regime that would improve their symptoms, therefore the investigation of agents that may deal with its more serious aspects is an important medical field for research. The cardiovascular consequences associated with the syndrome and some of the therapeutic approaches are discussed. The different agents can be divided into several groups: Inorganic/ organic: Zinc complexes with garlic components as insulino-mimetics; Selenium as antioxidant; Copper, Zinc and Manganese as microcomponents of antioxidant enzymes. Organic: Natural or Synthetic: Glycine is effective in lowering blood pressure, TBARS, intra-abdominal fat tissue and triglycerides in sucrose-fed rats. Pharmaceutical products: Fibrates, Lipid-lowering drugs. Antidiabetics. Anti-gout agents. On the other hand there are natural products such as those of animal origin: Sex hormones (also synthetic) used in the problems of menopause and hypoandrogenism frequently found in the MS, antioxidant Omega-3-oils (fish oils) or Vegetal: for example Digitalis pupurea, century-old cardiovascular medication as well as Magnolia officinalis; Spirulina maxima with beneficial effects as antioxidant and lipid-lowering agent, among others. Prickly Pear Cacti. (Opuntia Ficus- Indica Cochlospermum vitifolium (Willd.) Spreng) whose many properties against diabetes and hypercholesterolemia have been empirically known for many years. Perezone (from Perezia plants, a.k.a. Peonia) described as an antiplatelet aggregating agent. The mixed elements in the Mediterranean diet: Fish, salads (peppers, tomatoes), olive oil, garlic, red wine which combines fish oils, garlic and avocado as well as antioxidants from the rest of its components.

Early changes in gene expression that influence the course of primary glomerular disease.

Serial changes in glomerular capillary loop gene expression were used to uncover mechanisms contributing to primary glomerular disease in rat models of passive Heymann nephritis and puromycin nephrosis. Before the onset of proteinuria, podocyte protein-tyrosine phosphatase (GLEPP1) expression was transiently decreased in the nephrosis model, whereas the immune costimulatory molecule B7.1 was stimulated in both models. To relate these changes to the development of proteinuria, the time of onset and intensity of proteinuria were altered. When the models were induced simultaneously, proteinuria and anasarca occurred earlier with the collapse of glomerular capillary loops. Upregulation of B7.1 with the downregulation of GLEPP1, Wilms' tumor gene (WT1), megalin, and vascular endothelial growth factor started early and persisted through the course of disease. In the puromycin and the combined models, changes in GLEPP1 expression were corticosteroid-sensitive, whereas B7.1, WT1, vascular endothelial growth factor, and most slit diaphragm genes involved later in the combined model, except podocin, were corticosteroid-resistant. There was a very early increase in the nuclear expression of podocyte transcription factors ZHX2 and ZHX1 that may be linked to the changes in gene expression in the combined proteinuric model. Our studies suggest that an early and persistent change in mostly steroid-resistant glomerular gene expression is the hallmark of severe and progressive glomerular disease.

La atención continuada al enfermo crítico y el modelo andaluz. Réplica / Critical patient continuous care and the Andalusian model. Reply

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Pulmonary lymphoid lesions in an experimental model of collapsing glomerulopathy in rats.

UNLABELLED: The characterization of lung damage in an experimental model of collapsing glomerulopathy (CG) in rats is described. METHODS: 12 rats were divided into two groups and injected intravenously (iv) with 1 mg/saline in a final volume of 1 ml/ day in the tail vein for 5 days, with fractionated serum from control and CG subjects. Proteinuria was quantified, and the Glomerular filtration rate was calculated based on creatinine clearance (CC). Rats were sacrificed by perfusion fixation at day 5. RESULTS: Rats injected with serum from CG patients developed proteinuria (p<0.001). A decrease in CC (0.68+/-0.19) in these rats was also observed. Glomerular tuft retraction and mesangial proliferation was observed in all rats receiving serum from the CG patients. Peribronchiolar infiltrate integrated mainly by lymphocytes, was identified in all CG rats. In some areas this infiltration disrupted the basement membrane and damaged the epithelium. No histopathological abnormalities in the kidney or lungs were found in rats receiving control serum. CONCLUSION: Patchy pulmonary lymphoid infiltrates were found in the CG model. Up to now there was no information about pulmonary lymphoid infiltration in CG patients. Besides fluid overload due to renal insufficiency or a nephrotic syndrome, other causes of pulmonary involvement in CG patients should be explored.

Situación actual de los Servicios de Urgencias Hospitalariosen España (y IV): Áreas de Observación / Present situation of the Hospital Emergency Care Services in Spain (and IV): Observation Areas

Objetivos: Analizar la estructura física, los recursos materiales y humanos de las áreas de observación de los Servicios de Urgencias hospitalarios (SUH) españoles. Métodos: Estudio observacional descriptivo, realizado mediante encuesta por correo, en el que fueron incluidos 340 SUH españoles. A través de 134 variables, se recogió información sobre los SUH. En este artículo se analiza únicamente las variables correspondientes a las áreas de observación. Resultados: El 78 por ciento de los 190 SUH analizados disponen de área de observación. La proporción de ingresos en observación respecto al total de urgencias asistidas es del 6,3 por ciento. La extensión media de estas áreas es de 90 m2 (AI=40-180), con una media de 7 camas (AI=5-12). La relación cama/urgencias asistidas al año es de 1/5.687. El número de camas del área de observación fue considerado adecuado en el 13,3 por ciento, excesivo en el 30,5 por ciento y deficitario en el 56,2 por ciento restante. La estancia media en observación es de 14,8 horas (DE=3,2). En casi el 40 por ciento de estas áreas la estancia media sobrepasa las 24 horas. Sólo el 32,4 por ciento de las áreas de observación son atendidas por médicos dedicados exclusivamente a ellas, con un índice cama/médico de 7,3 (DE=5,4). Respecto al personal de enfermería, únicamente 30,4 por ciento de las áreas de observación analizadas disponen de ATS con dedicación específica al área, atendiendo cada ATS una media de 6,6-7,4 pacientes. Los médicos residentes están presentes en el 23 por ciento de las áreas de observación, con un índice cama de observación/residente de 9,2. Los criterios más frecuentes de ingreso en observación son la duda diagnóstica (89,2 por ciento) y la instauración del tratamiento urgente (81,8 por ciento). Conclusiones: 1) La mayor parte de los Servicios de urgencias hospitalarios de nuestro país cuentan con área de observación. 2) La estancia media de los pacientes en observación es mayor de la deseada en una importante proporción de las áreas analizadas. 3) Debe potenciarse la presencia en las áreas de observación de personal sanitario con dedicación exclusiva a esta área. 4) Igualmente, los recursos materiales deben ser de uso exclusivo para el área de observación. 5) Los criterios más frecuentes de ingreso en observación son la duda diagnóstica y la instauración de tratamiento urgente (AU)

Situación actual de los Servicios de Urgencias Hospitalariosen España (III): Recursos materiales y humanos. Perfilprofesional del médico de Urgencias / Present situation of the Hospital Emergency Care Services in Spain (III): Material and human resources. Professional profile of the Emergency Physician

Objetivos: Analizar los recursos materiales y humanos de los servicios de urgencias hospitalarios (SUH) españoles. Igualmente, se desea conocer el perfil profesional del médico de urgencias. Métodos: Estudio observacional descriptivo, realizado mediante encuesta por correo, en el que fueron incluidos 340 SUH españoles. A través de 134 variables, se recogió información de los SUH. En este artículo se analiza únicamente las variables correspondientes a conseguir los objetivos del estudio. Resultados: Se ha obtenido una tasa de respuesta de 56 por ciento (190 SUH). Se observó la existencia de relación lineal significativa (p < 0,001) entre el número de monitores y el número de urgencias asistidas anualmente en los SUH (r=0,49), así como para el número de desfibriladores (r=0,44) y para el número de electrocardiógrafos (r=0,51). Sólo 22,6 por ciento disponen de gasómetro arterial de uso exclusivo y 66,8 por ciento disponen de marcapasos externos. En el 92 por ciento de SUH existe un responsable específico de urgencias. Este desempeña más frecuentemente el cargo de Coordinador (52,3 por ciento), siendo Jefes de Servicio sólo el 29,3 por ciento. El 86 por ciento de SUH disponen de facultativos propios que permiten garantizar una completa cobertura asistencial. Los 190 SUH objeto de estudio cuentan con un total de 1.712 facultativos propios de urgencias (FPU). La mediana de FPU por SUH fue de 8 (AI= 6-11), con unos límites de rango de 1 a 44. El 63,7 por ciento de los SUH tienen una adecuada dotación de médicos de urgencias, siendo los hospitales de mayor nivel los más deficitarios. En su mayoría los FPU son médicos generales (56,5 por ciento) y médicos de familia (21 por ciento). La situación de interinidad es la situación laboral más frecuente (43,5 por ciento). Su forma de trabajo más habitual (50,3 por ciento) es por guardias médicas y turnos de mañana, tarde y noche. Las ausencias laborales por bajas o vacaciones reglamentarias de los FPU no se cubre en una importante proporción de casos. La mayoría de los residentes de guardia en el SUH son residentes de primer y segundo años de formación. Sobre este estamento recae buena parte de la labor asistencial de los SUH (fundamentalmente por la tarde y noche). Su capacidad de decisión depende de su año de residencia. En el 48 por ciento de SUH no hay responsable directo de la sala de espera de enfermos. En el 66,8 por ciento de SUH se realiza triage, siendo el profesional más implicado en el mismo el ATS (68,25 por ciento). Conclusiones: 1) Los pequeños coeficientes de correlación obtenidos entre el número de monitores, desfibriladores y electrocardiógrafos y la demanda asistencial de los SUH puede reflejar una inadecuada dotación cuantitativa de estos recursos materiales. 2) Se observa que existe mayor carga asistencial por FPU en los hospitales del nivel I. 3) Los SUH de nivel I son los proporcionalmente más deficitarios en dotación de facultativos. 4) La forma más habitual de trabajo en los SUH encuestados es mediante turnos de 8 horas y guardias. 5) Los médicos internos residentes tienen como actividad fundamental en los SUH la realización de guardias médicas, siendo principalmente residentes de los primeros y segundo año de formación, con una variable capacidad de decisión. (AU)

Situación actual de los Servicios de Urgencias Hospitalariosen España (II): Actividad asistencial, docente e investigadora / Present situation of the Hospital Emergency Care Services in Spain (II): Assistential, teaching/training and research activities

Objetivos: Analizar la actividad asistencial, docente e investigadora de los servicios de urgencias hospitalarios (SUH) españoles. Métodos: Estudio observacional descriptivo, realizado mediante encuesta por correo, en el que fueron incluidos 340 SUH españoles. A través de 134 ítems, se recogió información sobre los SUH,. En este artículo se analiza únicamente los ítems correspondientes a la actividad asistencial, docente e investigadora. Resultados: Se ha obtenido una tasa de respuesta de 56 por ciento (190 SUH). La mediana de urgencias asistidas al año en cada SUH fue de 38.049,5 (AI=17.500-61.000), oscilando entre 1.154 y 173.022 urgencias asistidas. La presión media de urgencias es de 61 por ciento (AI=49,8-70 por ciento), oscilando entre 1,4 y 106 por ciento. La proporción media de ingresos urgentes respecto al total de urgencias asistidas es de 14,3 por ciento (DE=6,5), oscilando entre 1 por ciento y 59,6 por ciento. La proporción media de decisiones de ingreso al año fue de 15,94 por ciento (DE=7,1), oscilando entre 2 y 59,6 por ciento (IC 95 por ciento= 14,8 a 17,1), sin diferencias significativas entre los 3 niveles hospitalarios asistenciales. La consulta al especialista se realiza por término medio en un 23,1 por ciento de los casos (DE=15,3). La proporción de pacientes remitidos con informe de derivación es de menos del 25 por ciento. En el 76,3 por ciento disponen y se aplican protocolos de actuación urgente. El tiempo medio de permanencia del paciente en Urgencias fue de 121 minutos (EE=11,8), con unos límites de rango de 2 a 320 minutos. Los intervalos de tiempo de demora de exploraciones complementarias más frecuentes en los SUH encuestados fueron de 30-60 minutos para los datos de laboratorio en el 54,4 por ciento de SUH, menor de 30 minutos para la radiología (57,5 por ciento) y la gasometría arterial (88,1 por ciento).Respecto a la actividad docente e investigadora, en el 61,6 por ciento de SUH existe algún tipo de sesión periódica. La rotación de médicos residentes por los SUH existe en el 38,4 por ciento de los mismos, con una duración media de 2 meses (DE=1,8). El 45,8 por ciento de los SUH contestaron haber publicado algún trabajo científico durante el período de estudio, con una media de 4 trabajos (DE=3,9) por SUH, la mayor parte (81 por ciento) en revistas nacionales. 64,7 por ciento respondieron haber presentado comunicaciones a congresos científicos, con una media de 5,4 (DE=7,3) por SUH. Conclusiones: 1) El análisis de la actividad asistencial de los SUH incluidos en el estudio muestra en general una distribución homogénea entre los distintos niveles asistenciales así como entre los diferentes ámbitos geográficos de nuestro país. 2) Una gran proporción de pacientes acuden a los SUH de forma espontánea obviando los dispositivos extrahospitalarios.3) Se constata el deficiente registro que en la mayoría de SUH se tiene de los tiempos asistenciales analizados. 4) Existe una importante actividad docente e investigadora en los SUH españoles (AU)