Critical update for the clinical use of L-carnitine analogs in cardiometabolic disorders

Acetyl-L-carnitine (ALC) and propionyl-L-carnitine (PLC) are two naturally occurring carnitine derivates formed by carnitine acetyltransferase. The beneficial cardiovascular effects of ALC and PLC have been extensively evaluated in animals and humans during the last 20 years. For instance, many clinical trials have suggested ALC and PLC as potential strategies in the management of peripheral arterial disease, heart and cerebral ischemia, and congestive heart failure. As a result, several experts have already aimed to revise the clinical evidence supporting the therapeutic use of ALC and PLC. On the basis of their conclusions, our aim was a critical review of the effectiveness of ALC and PLC in the treatment of cardiovascular diseases. Type 2 diabetes mellitus is an independent risk factor for the development of cardiovascular disease. Therefore we also describe recent studies that have addressed the emerging use of ALC and PLC amelioration of the insulin resistant state and its related morbidities

Oral supplementation of propionyl-l-carnitine reduces body weight and hyperinsulinaemia in obese Zucker rats

Propionyl-l-carnitine (PLC) is an SCFA esterified to carnitine that plays an important role in fatty acid oxidation and energy expenditure, in addition to having a protective effect on the endothelium. In order to evaluate the effect of PLC on an animal model of obesity, insulin resistance and, consequently, endothelial dysfunction, lean and obese Zucker rats (OZR) received either vehicle- or PLC-supplemented drinking water (200mg/kg per d) for 20 weeks. Body weight, food intake, systolic blood pressure and heart rate were controlled weekly and an oral glucose tolerance test was performed. Fasting glucose, TAG, cholesterol, HDL, NEFA, adiponectin and insulin were analysed in serum. Visceral adipose tissue and liver were weighed and liver TAG liver composition was evaluated. Endothelial and vascular functions were assessed in the aorta and small mesenteric arteries by response to acetylcholine, sodium nitroprusside and phenylephrine (Phe); NO participation was evaluated after incubation with the NO synthase (NOS) inhibitor NG-nitro-l-arginine methyl ester (l-NAME) and endothelial NOS protein expression by Western blotting. PLC decreased body-weight gain, food intake, adiposity, insulin serum concentration and TAG liver content and improved insulin resistance. Aortae from OZR receiving either vehicle or PLC exhibited a lower contractile response to Phe. PLC-treated OZR showed an enhanced release of endothelial NO upon the adrenergic stimulation. The protection of vascular function found after treatment with PLC in an animal model of insulin resistance supports the necessity of clinical trials showing the effect of l-carnitine supplements on metabolic disorders.Junta de Andalucía CTS-17

Propionyl-L-carnitine corrects metabolic and cardiovascular alterations in diet-induced obese mice and improves liver respiratory chain activity

Aims: Obesity is a primary contributor to acquired insulin resistance leading to the development of type 2 diabetes and cardiovascular alterations. The carnitine derivate, propionyl-L-carnitine (PLC), plays a key role in energy control. Our aim was to evaluate metabolic and cardiovascular effects of PLC in diet-induced obese mice. Methods: C57BL/6 mice were fed a high-fat diet for 9 weeks and then divided into two groups, receiving either free- (vehicle-HF) or PLC-supplemented water (200 mg/kg/day) during 4 additional weeks. Standard diet-fed animals were used as lean controls (vehicle-ST). Body weight and food intake were monitored. Glucose and insulin tolerance tests were assessed, as well as the HOMAIR, the serum lipid profile, the hepatic and muscular mitochondrial activity and the tissue nitric oxide (NO) liberation. Systolic blood pressure, cardiac and endothelial functions were also evaluated. Results: Vehicle-HF displayed a greater increase of body weight compared to vehicle-ST that was completely reversed by PLC treatment without affecting food intake. PLC improved the insulin-resistant state and reversed the increased total cholesterol but not the increase in free fatty acid, triglyceride and HDL/LDL ratio induced by high-fat diet. Vehicle-HF exhibited a reduced cardiac output/body weight ratio, endothelial dysfunction and tissue decrease of NO production, all of them being improved by PLC treatment. Finally, the decrease of hepatic mitochondrial activity by high-fat diet was reversed by PLC. Conclusions: Oral administration of PLC improves the insulin-resistant state developed by obese animals and decreases the cardiovascular risk associated to this metabolic alteration probably via correction of mitochondrial function

Stabilized municipal sewage sludge addition to improve properties of an acid mine soil for plant growth

Purpose: Degraded soils, such as those encountered in areas of mine activities, need to be ameliorated by liming to correct soil acidity and by addition of organic inputs to improve soil properties and fertility. Materials and methods: Non-amended mine soil and soil amended with stabilized sewage sludge were incubated for 45 days. Soil physicochemical and biological indicators were periodically measured along incubation and other enzyme activities at the end of incubation. In improved soils, a study of plant development in 250-g pots was carried out with three vegetal species: tomato, rye grass and ahipa. Germination and mortality rates, biomass production and photosynthetic pigments were measured. Results and discussion: Soil incubation with sewage sludge slightly increased soil pH and led to an enhancement of soil electrical conductivity, organic carbon and dehydrogenase activity, especially for the higher doses (5 and 10%). However soil respiration was more promoted with the 2% dose, pointing to a possible toxic effect of the sludge. At the end of incubation, physicochemical and biological properties were in general enhanced. Biomass production was improved in tomato and rye grass by sewage sludge addition (more at the 2% dose), whilst ahipa growth was not affected by sewage sludge treatments. Tomato mortality reached 73% with high sludge doses (10%). Conclusions: According to this set of parameters, amendment with sewage sludge of a limed acid mine soil would be considered as a good strategy for soil amelioration in view of plant establishment and development.Junta de Andalucía P10-RNM581

Efectos del Cu en la absorción de nutrientes en una especie vegetal procedente de suelos mineros

La intensa explotación de los recursos naturales acontecida a partir de la mitad del siglo pasado ha propiciado una degradación ambiental progresiva. En el caso de las explotaciones mineras se generan grandes áreas en las que los suelos ven reducida, o incluso mermada, su fertilidad. En el área minera de Riotinto se aprecian vastas áreas con suelos que presentan un bajo contenido en nutrientes, pH ácido, baja capacidad de intercambio catiónico y un enriquecimiento en metales, entre los que cabe destacar el Cu. A pesar de la existencia de unas condiciones edáficas desfavorables, diversas especies vegetales han conseguido establecerse en la zona evitando de este modo parte de la erosión y degradación del suelo. Entre estas especies cabe destacar Erica australis y Erica andevalensis. Para estudiar el efecto que los niveles de Cu disponible pueden tener sobre la nutrición mineral y el crecimiento de esta especie, plántulas de E. australis fueron cultivadas en solución nutritiva y expuestas a diferentes concentraciones de Cu (50, 100 y 200 M) bajo condiciones controladas. La respuesta a los diferentes niveles de Cu fue medida determinando la absorción de macro- y micro- nutrientes en las diferentes partes vegetales, el contenido hídrico relativo de la parte área y de la raíz y la variación de biomasa fresca. El aumento de Cu en la solución nutritiva induce una disminución de la biomasa y del contenido hídrico y favorece la absorción de la mayoría de los nutrientes

Respuesta de dos especies arbustivas de suelos mineros: bioacumulación y translocación de elementos traza

La mayoría de las especies vegetales que se han establecido en el área minera de Riotinto se han adaptado a las condiciones edafo-climáticas de la zona que son hostiles para muchas plantas. Para la revegetación de estas áreas se requiere información acerca de la respuesta de las comunidades vegetales nativas a las condiciones de estrés existentes. En este trabajo se ha evaluado la respuesta de Erica australis y Nerium oleander, especies espontáneas y abundantes en el área de Riotinto, frente a elementos traza presentes en los suelos (Cd, Cu, Cr, Ni, Pb y Zn) en concentraciones espacialmente variables, y en algunos casos superiores a los niveles de referencia. Se evaluó la distinta capacidad de acumulación/translocación de dichos metales en las dos especies mediante los factores de bioacumulación (FB = Mhoja / Msuelo) y de translocación (FT = Mhoja / Mraiz). En general, ninguna especie muestra acumulación de metales en las hojas (FB < 1). Un caso a señalar es el del Pb, que a pesar de las elevadas concentraciones en las que se encuentra en el suelo, no es translocado a la parte aérea de ninguna de las especies debido a mecanismos de exclusión. En cambio, cantidades significativas de Ni se translocan de la raíz a la parte aérea en N. oleander. Los valores de Cr, Ni y Pb encontrados en la parte aérea de E. australis y de Cd, Ni, Pb y Zn en N. oleander son superiores a los que se consideran normales para las plantas. Los resultados indican que, aunque las dos especies presentan diferente comportamiento frente a los elementos traza, ambas muestran propiedades adecuadas para su uso en fitorremediación

Riesgos derivados de la presencia de residuos mineros: Disponibilidad de metales en minas abandonadas

La minería en Andalucía ha dado lugar a la creación de entornos, formados por sólidos de desecho, que forman lo que se conoce como tecnosoles y que pueden contener elementos potencialmente tóxicos para los recursos hídricos y biológicos; llegando incluso a suponer un riesgo para la salud. Los metales más abundantes en el entorno de Riotinto son Cd (1-50 mg kg-1), Pb (80-52000 mg kg-1) y Cu (20-2000 mg kg-1) con una alta variabilidad espacial, en forma de parches. En el área de Alquife, el contenido de estos metales es menor (Cd, 1-11 mg kg-1; Cu, 30-60 mg kg-1; Pb, 6-12 mg kg-1) y su distribución espacial es más homogénea. En este trabajo, se presenta una primera aproximación al riesgo de toxicidad de estos metales para organismo biológicos, especialmente las plantas, estimados a partir de la fracción extraíble con EDTA. Las características físico-químicas de los suelos, en especial el pH, ácido en Ritointo y ligeramente básico en Alquife, controlan la dinámica de las especies químicas en la fase sólida del suelo y, por tanto, su potencial movilidad. En Alquife, el metal más biodisponible es el Cd, mientras que los otros metales están disponibles en cantidades < 2% del total. En cambio, en Riotinto, la biodisponibilidad puede llegar a superar el 50% en algunos puntos, y la secuencia es Cu>Pb>Zn>Cd

How are mammalian methionine adenosyltransferases regulated in the liver? A focus on redox stress

S-adenosylmethionine synthesis is a key process for cell function, and needs to be regulated at multiple levels. In recent years, advances in the knowledge of methionine adenosyltransferases have been significant. The discovery of nuclear localization of these enzymes suggests their transport to provide the methyl donor, S-adenosylmethionine, for DNA and histone methyltransferases in epigenetic modifications, opening new regulatory possibilities. Previous hypotheses considered only the cytoplasmic regulation of these enzymes, hence the need of an update to integrate recent findings. Here, we focus mainly on the liver and redox mechanisms, and their putative effects on localization and interactions of methionine adenosyltransferases.Ministerio de Economía y Competitividad (BFU2008-00666 and BFU2009-08977 to M.A.P., and SAF2009-11642 and SAF2012-36519 to D.P.S.) and Instituto de Salud Carlos III (RETICS RD12/0013/0008 to D.P.S. and FIS PI12/01196 to L.A.).Peer reviewe