Pulmonary arterial dysfunction in insulin resistant obese Zucker rats

<p>Abstract</p> <p>Background</p> <p>Insulin resistance and obesity are strongly associated with systemic cardiovascular diseases. Recent reports have also suggested a link between insulin resistance with pulmonary arterial hypertension. The aim of this study was to analyze pulmonary vascular function in the insulin resistant obese Zucker rat.</p> <p>Methods</p> <p>Large and small pulmonary arteries from obese Zucker rat and their lean counterparts were mounted for isometric tension recording. mRNA and protein expression was measured by RT-PCR or Western blot, respectively. K_Vcurrents were recorded in isolated pulmonary artery smooth muscle cells using the patch clamp technique.</p> <p>Results</p> <p>Right ventricular wall thickness was similar in obese and lean Zucker rats. Lung BMPR2, K_V1.5 and 5-HT_2Areceptor mRNA and protein expression and K_Vcurrent density were also similar in the two rat strains. In conductance and resistance pulmonary arteries, the similar relaxant responses to acetylcholine and nitroprusside and unchanged lung eNOS expression revealed a preserved endothelial function. However, in resistance (but not in conductance) pulmonary arteries from obese rats a reduced response to several vasoconstrictor agents (hypoxia, phenylephrine and 5-HT) was observed. The hyporesponsiveness to vasoconstrictors was reversed by L-NAME and prevented by the iNOS inhibitor 1400W.</p> <p>Conclusions</p> <p>In contrast to rat models of type 1 diabetes or other mice models of insulin resistance, the obese Zucker rats did not show any of the characteristic features of pulmonary hypertension but rather a reduced vasoconstrictor response which could be prevented by inhibition of iNOS.</p

Caracterización de la brisa cantábrica

Ponencia presentada en: IV Congreso de la Asociación Española de Climatología "El Clima entre el Mar y la Montaña", celebrado en Santander del 2 al 5 de noviembre de 2004.[ES]Las brisas constituyen un elemento fundamental del clima en las zonas costeras. En el desencadenamiento de las mismas parece demostrado que el viento de retorno hacia la mar es un factor de superior importancia a la de otros, generalmente de tipo térmico. Se han estudiado regímenes de brisas en la costa cantábrica de Santander (España) con casos de cinco años, entre mayo y setiembre, analizando los datos de superficie y aerológicos. Primeramente se muestran los criterios de selección de casos a efectos de discernir claramente entre un día de brisa genuina de muchos otros que aparentemente lo son, por la coincidencia en la dirección dominante del viento, pero que tan solo muestran una oscilación diaria en la fuerza -de forma similar a la brisa- motivada por un idéntico ciclo diario en la intensidad de la turbulencia en capas bajas de la atmósfera.[EN]Breezes are a main element of climate in coastal areas. Has been demostrated than the role of the upper wind to offshore is more important than others thermic factors. Regimenes of breeze have been studied along the coast of Santander (north Spain) over five years cases, from may to september, analyzing low and high level data. First, the selection criteria are showed in the way to identify a genuine breeze day among others that appear to be caused by the wind´s main direction, but they only show a daily oscillation in strength –similar to the breeze– caused by an identic daily cycle of the turbulence intensity in the low atmospheric layers

Caracterización del oleaje en las aguas costeras del Cantábrico

Ponencia presentada en: IV Congreso de la Asociación Española de Climatología "El Clima entre el Mar y la Montaña", celebrado en Santander del 2 al 5 de noviembre de 2004.[ES]En este trabajo, se muestra cómo se modifica el oleaje al entrar en las aguas costeras del Cantábrico debido a su refracción en aguas someras. Asimismo, se incluye una breve descripción, tanto geográfica como climatológica, de la zona marítima de estudio.[EN]This text aims to explain how the surge is modificated when it comes into coastal waters, in Cantabrian Sea (North of Spain), because of the refraction’s surge in shallow waters. It also contains a brief description of maritime study area, both climatologic and geographic

Climatología de tormentas veraniegas en Cantabria, Asturias y País Vasco

Ponencia presentada en: IV Congreso de la Asociación Española de Climatología "El Clima entre el Mar y la Montaña", celebrado en Santander del 2 al 5 de noviembre de 2004.[ES]Esta comunicación pretende exponer una serie de situaciones sinópticas de verano, que se caracterizan por ser las más favorables a la aparición de fenómenos tormentosos. El estudio climatológico se realizó como parte de un trabajo destinado a caracterizar y mejorar las técnicas de predicción de tormentas en la zona de estudio. Dentro de este trabajo, existe además un tratamiento estadístico de diversos índices de inestabilidad que se utilizan en la predicción operativa diaria.[EN]This text aims to explain a series of synoptic summer situations which are characterised for being most favourable for producing stormy weather. The climatological study was carried out as part of a project designed to improve forecast techniques within the study area. Apart from this, there is also a statistical study of several instability indexes which are used in daily operational forecasting

The LKB1-AMPK-α1 signaling pathway triggers hypoxic pulmonary vasoconstriction downstream of mitochondria

International audienceHypoxic pulmonary vasoconstriction (HPV), which aids ventilation-perfusion matching in the lungs, is triggered by mechanisms intrinsic to pulmonary arterial smooth muscles. The unique sensitivity of these muscles to hypoxia is conferred by mitochondrial cytochrome c oxidase subunit 4 isoform 2, the inhibition of which has been proposed to trigger HPV through increased generation of mitochondrial reactive oxygen species. Contrary to this model, we have shown that the LKB1-AMPK-α1 signaling pathway is critical to HPV. Spectral Doppler ultrasound revealed that deletion of the AMPK-α1 catalytic subunit blocked HPV in mice during mild (8% O2) and severe (5% O2) hypoxia, whereas AMPK-α2 deletion attenuated HPV only during severe hypoxia. By contrast, neither of these genetic manipulations affected serotonin-induced reductions in pulmonary vascular flow. HPV was also attenuated by reduced expression of LKB1, a kinase that activates AMPK during energy stress, but not after deletion of CaMKK2, a kinase that activates AMPK in response to increases in cytoplasmic Ca2+ Fluorescence imaging of acutely isolated pulmonary arterial myocytes revealed that AMPK-α1 or AMPK-α2 deletion did not affect mitochondrial membrane potential during normoxia or hypoxia. However, deletion of AMPK-α1, but not of AMPK-α2, blocked hypoxia from inhibiting KV1.5, the classical "oxygen-sensing" K+ channel in pulmonary arterial myocytes. We conclude that LKB1-AMPK-α1 signaling pathways downstream of mitochondria are critical for the induction of HPV, in a manner also supported by AMPK-α2 during severe hypoxia

Production of spinach in intensive Mediterranean horticultural systems can be sustained by organic-based fertilizers without yield penalties and withlow environmental impacts

Agricultural production of leafy vegetables in Mediterranean countries aims to achieve high yields without elevated nitrate contents in the edible parts. This implies an adjusted nutrient management, especially of nitrogen (N), in irrigated horticultural systems under semiarid conditions. These horticultural systems are highly relevant in SE Spain from an economic perspective. However, the management of N fertilizer, generally applied in large amounts (150–250 kg N ha−1 in a split application), could trigger losses of reactive N to the environment. The use of novel fertilizers may fulfill the nitrogen requirements of the crop, but should also help to decrease the environmental impacts of production, thus achieving carbon-neutral horticultural systems through (e.g.) enhancement of carbon (C) stocks and greenhouse gases (GHG) emission abatement. In this experiment, eight different fertilizing scenarios at a normalized N application rate of 150 kg N ha−1 were assessed in terms of crop yields, nutrients uptake, C stocking capacity, and yield-scaled GHG emissions. Inorganic NPK fertilizers, digestates, biosolids, composts, and vermicomposts were included among this set of fertilizers. Our results show that organic-based stabilized materials, especially composts, lowered the NO3 − concentration in spinach leaves, in comparison to organic raw materials and synthetic fertilizers. They also produced yields similar to those of slow-release synthetic fertilizers, but with a significant increase in soil organic C 61 days after application. In general, N2O emissions were positively affected by the treatments. Nevertheless, direct N2O emissions were generally low (the highest emission factor, 0.13, being for the biosolid treatment) due to the combined mitigating effect of both the edapho-climatic conditions and the management practices. In general, cumulative CO2 emissions were high in all organic scenarios compared to the control treatment (299 kg C-CO2 ha−1), the highest values being observed in the treatment with biosolid (589 kg C-CO2 ha−1), probably due to differences in the labile organic C contents. In conclusion, some of the organic-based treatments showed multiple positive effects: on crop quality (i.e. leaf N content), crop yields, and GHG mitigation potential. Based on our results, the use of these materials represents an optimized N fertilizer strategy to help achieve a circular economy, by closing nutrient loops and decreasing the environmental impacts of horticultural production systems in semiarid regions of southern Europ

The Flavonoid Quercetin Reverses Pulmonary Hypertension in Rats

Quercetin is a dietary flavonoid which exerts vasodilator, antiplatelet and antiproliferative effects and reduces blood pressure, oxidative status and end-organ damage in humans and animal models of systemic hypertension. We hypothesized that oral quercetin treatment might be protective in a rat model of pulmonary arterial hypertension. Three weeks after injection of monocrotaline, quercetin (10 mg/kg/d per os) or vehicle was administered for 10 days to adult Wistar rats. Quercetin significantly reduced mortality. In surviving animals, quercetin decreased pulmonary arterial pressure, right ventricular hypertrophy and muscularization of small pulmonary arteries. Classic biomarkers of pulmonary arterial hypertension such as the downregulated expression of lung BMPR2, Kv1.5, Kv2.1, upregulated survivin, endothelial dysfunction and hyperresponsiveness to 5-HT were unaffected by quercetin. Quercetin significantly restored the decrease in Kv currents, the upregulation of 5-HT2A receptors and reduced the Akt and S6 phosphorylation. In vitro, quercetin induced pulmonary artery vasodilator effects, inhibited pulmonary artery smooth muscle cell proliferation and induced apoptosis. In conclusion, quercetin is partially protective in this rat model of PAH. It delayed mortality by lowering PAP, RVH and vascular remodeling. Quercetin exerted effective vasodilator effects in isolated PA, inhibited cell proliferation and induced apoptosis in PASMCs. These effects were associated with decreased 5-HT2A receptor expression and Akt and S6 phosphorylation and partially restored Kv currents. Therefore, quercetin could be useful in the treatment of PAH.This work was supported by grants and fellowships by the Spanish Ministerio de Economia y Competitividad (SAF2011-28150 to F.P-V, SAF2010-22066-C02-01 to JD, and −02 to AC); Instituto de Salud Carlos III Red HERACLES RD06/0009 to JD; Miguel Servet Program CP12/03304 to LM; predoctoral grants BES-2012-051904 to DMS, CM, JMS, and PG; and Junta de Andalucia (Proyecto de excelencia, P12-CTS-2722)

Adiciones y revisiones al Atlas de la flora vascular silvestre de Burgos

Se mencionan 31 táxones con citas y/o comentarios referidos a su existencia en la provincia de Burgos. De ellos 8 suponen una novedad para el catálogo provincial.Additions and revisions for the “Atlas de la flora vascular silvestre de Burgos”, IX. 31 Taxa with either quotations or remarks, related to their existence within the province of Burgos, are mentioned. 8 out of these aforementioned ones mean a novelty value for the provincial catalogue

ERK and mTORC1 Inhibitors Enhance the Anti-Cancer Capacity of the Octpep-1 Venom-Derived Peptide in Melanoma BRAF(V600E) Mutations

Melanoma is the main cause of skin cancer deaths, with special emphasis in those cases carrying BRAF mutations that trigger the mitogen-activated protein kinases (MAPK) signaling and unrestrained cell proliferation in the absence of mitogens. Current therapies targeting MAPK are hindered by drug resistance and relapse that rely on metabolic rewiring and Akt activation. To identify new drug candidates against melanoma, we investigated the molecular mechanism of action of the Octopus Kaurna-derived peptide, Octpep-1, in human BRAF(V600E) melanoma cells using proteomics and RNAseq coupled with metabolic analysis. Fluorescence microscopy verified that Octpep-1 tagged with fluorescein enters MM96L and NFF cells and distributes preferentially in the perinuclear area of MM96L cells. Proteomics and RNAseq revealed that Octpep-1 targets PI3K/AKT/mTOR signaling in MM96L cells. In addition, Octpep-1 combined with rapamycin (mTORC1 inhibitor) or LY3214996 (ERK1/2 inhibitor) augmented the cytotoxicity against BRAF(V600E) melanoma cells in comparison with the inhibitors or Octpep-1 alone. Octpep-1-treated MM96L cells displayed reduced glycolysis and mitochondrial respiration when combined with LY3214996. Altogether these data support Octpep-1 as an optimal candidate in combination therapies for melanoma BRAF(V600E) mutations

AMP-activated protein kinase inhibits K_v1.5 channel currents of pulmonary arterial myocytes in response to hypoxia and inhibition of mitochondrial oxidative phosphorylation

KEY POINTS: Progression of hypoxic pulmonary hypertension is thought to be due, in part, to suppression of voltage‐gated potassium channels (K(v)) in pulmonary arterial smooth muscle by hypoxia, although the precise molecular mechanisms have been unclear. AMP‐activated protein kinase (AMPK) has been proposed to couple inhibition of mitochondrial metabolism by hypoxia to acute hypoxic pulmonary vasoconstriction and progression of pulmonary hypertension. Inhibition of complex I of the mitochondrial electron transport chain activated AMPK and inhibited K(v)1.5 channels in pulmonary arterial myocytes. AMPK activation by 5‐aminoimidazole‐4‐carboxamide riboside, A769662 or C13 attenuated K(v)1.5 currents in pulmonary arterial myocytes, and this effect was non‐additive with respect to K(v)1.5 inhibition by hypoxia and mitochondrial poisons. Recombinant AMPK phosphorylated recombinant human K(v)1.5 channels in cell‐free assays, and inhibited K(+) currents when introduced into HEK 293 cells stably expressing K(v)1.5. These results suggest that AMPK is the primary mediator of reductions in K(v)1.5 channels following inhibition of mitochondrial oxidative phosphorylation during hypoxia and by mitochondrial poisons. ABSTRACT: Progression of hypoxic pulmonary hypertension is thought to be due, in part, to suppression of voltage‐gated potassium channels (K(v)) in pulmonary arterial smooth muscle cells that is mediated by the inhibition of mitochondrial oxidative phosphorylation. We sought to determine the role in this process of the AMP‐activated protein kinase (AMPK), which is intimately coupled to mitochondrial function due to its activation by LKB1‐dependent phosphorylation in response to increases in the cellular AMP:ATP and/or ADP:ATP ratios. Inhibition of complex I of the mitochondrial electron transport chain using phenformin activated AMPK and inhibited K(v) currents in pulmonary arterial myocytes, consistent with previously reported effects of mitochondrial inhibitors. Myocyte K(v) currents were also markedly inhibited upon AMPK activation by A769662, 5‐aminoimidazole‐4‐carboxamide riboside and C13 and by intracellular dialysis from a patch‐pipette of activated (thiophosphorylated) recombinant AMPK heterotrimers (α2β2γ1 or α1β1γ1). Hypoxia and inhibitors of mitochondrial oxidative phosphorylation reduced AMPK‐sensitive K(+) currents, which were also blocked by the selective K(v)1.5 channel inhibitor diphenyl phosphine oxide‐1 but unaffected by the presence of the BK(Ca) channel blocker paxilline. Moreover, recombinant human K(v)1.5 channels were phosphorylated by AMPK in cell‐free assays, and K(+) currents carried by K(v)1.5 stably expressed in HEK 293 cells were inhibited by intracellular dialysis of AMPK heterotrimers and by A769662, the effects of which were blocked by compound C. We conclude that AMPK mediates K(v) channel inhibition by hypoxia in pulmonary arterial myocytes, at least in part, through phosphorylation of K(v)1.5 and/or an associated protein