Involvement of cannabinoid signaling in vincristine-induced gastrointestinal dysmotility in the rat

[Background]: In different models of paralytic ileus, cannabinoid receptors are overexpressed and endogenous cannabinoids are massively released, contributing to gastrointestinal dysmotility. The antitumoral drug vincristine depresses gastrointestinal motility and a similar mechanism could participate in this effect. Therefore, our aim was to determine, using CB and CB antagonists, whether an increased endocannabinoid tone is involved in vincristine-induced gastrointestinal ileus. [Methods]: First, we confirmed the effects of vincristine on the gut mucosa, by conventional histological techniques, and characterized its effects on motility, by radiographic means. Conscious male Wistar rats received an intraperitoneal injection of vincristine (0.1-0.5 mg/kg), and barium sulfate (2.5 ml; 2 g/ml) was intragastrically administered 0, 24, or 48 h later. Serial X-rays were obtained at different time-points (0-8 h) after contrast. X-rays were used to build motility curves for each gastrointestinal region and determine the size of stomach and caecum. Tissue samples were taken for histology 48 h after saline or vincristine (0.5 mg/kg). Second, AM251 (a CB receptor antagonist) and AM630 (a CB receptor antagonist) were used to determine if CB and/or CB receptors are involved in vincristine-induced gastrointestinal dysmotility. [Key results]: Vincristine induced damage to the mucosa of ileum and colon and reduced gastrointestinal motor function at 0.5 mg/kg. The effect on motor function was particularly evident when the study started 24 h after administration. AM251, but not AM630, significantly prevented vincristine effect, particularly in the small intestine, when administered thrice. AM251 alone did not significantly alter gastrointestinal motility. [Conclusions]: The fact that AM251, but not AM630, is capable of reducing the effect of vincristine suggests that, like in other experimental models of paralytic ileus, an increased cannabinoid tone develops and is at least partially responsible for the alterations induced by the antitumoral drug on gastrointestinal motor function. Thus, CB1 antagonists might be useful to prevent/treat ileus induced by vincristine.This work was supported by Ministerio de Ciencia e Innovación (SAF2009-12422-C02-01, SAF2012-40075-C02-01), Universidad Rey Juan Carlos—Comunidad de Madrid (URJC-CM-2006-BIO-0604) and Comunidad de Madrid (S-SAL/0261/2006; S2010/BMD-2308).Peer Reviewe

Beneficial Effects of Bovine Milk Exosomes in Metabolic Interorgan Cross-Talk

Extracellular vesicles are membrane-enclosed secreted vesicles involved in cell-to-cell communication processes, identified in virtually all body fluids. Among extracellular vesicles, exosomes have gained increasing attention in recent years as they have unique biological origins and deliver different cargos, such as nucleic acids, proteins, and lipids, which might mediate various health processes. In particular, milk-derived exosomes are proposed as bioactive compounds of breast milk, which have been reported to resist gastric digestion and reach systemic circulation, thus being bioavailable after oral intake. In the present manuscript, we critically discuss the available evidence on the health benefits attributed to milk exosomes, and we provide an outlook for the potential future uses of these compounds. The use of milk exosomes as bioactive ingredients represents a novel avenue to explore in the context of human nutrition, and they might exert important beneficial effects at multiple levels, including but not limited to intestinal health, bone and muscle metabolism, immunity, modulation of the microbiota, growth, and development

Asociación obesidad e hiperplasia nodular focal (HNF) telangiectásica. Reevaluación de 24 casos.

La hiperplasia nodular focal no es una verdadera neo plasia. Es una respuesta regenerativa de los hepatocitos a una anomalía vascular. Se reevaluaron 24 casos diagnosticados y confirmados en el estudio anatomopatológico como hiperplasia nodular focal. Tres de los 24 casos fueron reclasificados como adenomas inflamatorios telangiectásico, vinculado con antecedentes de síndromes metabolicos y con imnumorreactividad frente a la Amiloide A. La presencia de ectasia vascular, dilatación sinusoidal, áreas de peliosis con signos inflamatorios focales o difusos asociados a inmunorreactividad frente al Amiloide A son signos histológicos que nos indican la presencia de adenomas hepatocelulares inflamatorios telangiectásicos antiguamente clasificados como hiperplasia nodular focal atípica. El antecedentes de obesidad u hígado graso, unido al incremento en la reactividad frente al Amiloide A caracteriza a los adenomas inflamatorios telan giec - tásicos

Pioglitazone modulates the vascular contractility in hypertension by interference with ET-1 pathway

Endothelin-1 (ET-1) is an important modulator of the vascular tone and a proinflammatory molecule that contributes to the vascular damage observed in hypertension. Peroxisome-proliferator activated receptors-γ (PPARγ) agonists show cardioprotective properties by decreasing inflammatory molecules such as COX-2 and reactive oxygen species (ROS), among others. We investigated the possible modulatory effect of PPARγ activation on the vascular effects of ET-1 in hypertension. In spontaneously hypertensive rats (SHR), but not in normotensive rats, ET-1 enhanced phenylephrineinduced contraction through ETA by a mechanism dependent on activation of TP receptors by COX-2- derived prostacyclin and reduction in NO bioavailability due to enhanced ROS production. In SHR, the PPARγ agonist pioglitazone (2.5 mg/Kg·day, 28 days) reduced the increased ETA levels and increased those of ETB. After pioglitazone treatment of SHR, ET-1 through ETB decreased ROS levels that resulted in increased NO bioavailability and diminished phenylephrine contraction. In vascular smooth muscle cells from SHR, ET-1 increased ROS production through AP-1 and NFκB activation, leading to enhanced COX-2 expression. These effects were blocked by pioglitazone. In summary, in hypertension, pioglitazone shifts the vascular ETA/ETB ratio, reduces ROS/COX-2 activation and increases NO availability; these changes explain the effect of ET-1 decreasing phenylephrine-induced contractionThis work was supported by the Spanish Ministerio de Ciencia, Innovación y Universidades (SAF2015-69294-R and SAF2016-80305-P), Instituto de Salud Carlos III (CIBER de Enfermedades Cardiovasculares, CB16.11.00286), Comunidad de Madrid (B2017/BMD-3676) and Fondo Europeo de Desarrollo Regional (FEDER) a way to build Europ

Zenker diverticulum. Report of two atypical cases and review of surgical alternatives

[ES]Introducción y objetivo: El divertículo de Zenker es una protrusión o hernia de la mucosa faríngea posterior en la unión faringoesofágica. El mecanismo etiopatogénico parece ser la relajación insuficiente del músculo cricofaríngeo. Es el divertículo esofágico más común y los síntomas predominantes son disfagia y aspiración. El tratamiento quirúrgico está indicado en pacientes sintomáticos. Existen diversas alternativas. Descripción del caso: Presentamos dos casos clínicos atípicos de divertículo de Zenker. El primero es un paciente de 56 años de edad que presenta un divertículo de Zenker asociado a un carcinoma de tiroides en el cual se lleva a cabo una tiroidectomía total y la exéresis del divertículo. El segundo caso es un paciente de 64 años pluripatológico intervenido en otro centro de un divertículo de Zenker mediante abordaje endoscópico, remitido a nuestro servicio por disnea, enfisema, neumomediastino y absceso cervicomediastínico a los 3 días de dicha intervención. Se realiza traqueotomía temporal y cervicotomía y evoluciona favorablemente. Discusión: El divertículo de Zenker es una patología rara con una prevalencia menor al 0,1%. Se disponen de varias alternativas quirúrgicas, tanto por cirugía abierta como por procedimientos endoscópicos. No hay casos descritos asociados a neoplasias tiroideas. Aunque las complicaciones postoperatorias son raras pueden ser muy graves. Conclusiones: El divertículo de Zenker es una patología infrecuente cuyo tratamiento quirúrgico no está exento de complicaciones. Hay varias alternativas terapéuticas, desde la cirugía abierta hasta la endoscopia rígida o flexible. Todos los abordajes han sido bien demostrados en manos experimentadas y ninguno en es claramente superior a los demás. [EN] Introduction and objective: Zenker`s diverticulum is a protusion or hernation of the posterior pharyngeal mucosa in the pharyngoesophageal junction. The etiopathogenic mechanism appears to be insufficient relaxation of the cricopharyngeal muscle. It`s the most common esophageal diverticulum and the predominant symptoms are dysphagia and aspiration. Surgical treatment is indicated in symptomatic patients. There are several alternatives. Case description: We present two atypical clinical cases of Zenker diverticulum. The first is a 56 yo patient diagnosed of Zenker´s diverticulum associated with thyroid carcinoma wich is performed a total thyroidectomy and excision of the diverticulum. The second case is a 64 yo pluripathological patient intervened in another center of Zenker`s diverticulum by endoscopic approach, wich is referred to our department with dyspnea, emphysema, pneumomediastinum and cervical abscess at 3 days of this intervention. Temporary tracheotomy and cervicotomy is performed and progressing favorably. Discussion: Zenker`s diverticulum is a rare pathology with a prevalence less than 0,1%. There are various surgical options both open surgery and the endoscopic procedures. There are no reported cases associated with thyroid neoplasms. Postoperative complications are rare and severe. Conclusions: Zenker`s diverticulum is a uncommon pathology and the surgical treatment is not without complications. There are various treatment options wich include open surgery and the rigid and flexible endoscopy. All approaches have been well proven in experienced hands and none is clearly superior to others

Quality More Than Quantity: The Use of Carbohydrates in High-Fat Diets to Tackle Obesity in Growing Rats

This research was supported by funds provided by the Abbott Laboratories S.A.Childhood obesity prevention is important to avoid obesity and its comorbidities into adulthood. Although the energy density of food has been considered a main obesogenic factor, a focus on food quality rather that the quantity of the different macronutrients is needed. Therefore, this study investigates the effects of changing the quality of carbohydrates from rapidly to slowly digestible carbohydrates on metabolic abnormalities and its impact on obesity in growing rats fed a high-fat diet (HFD). Growing rats were fed on HFD containing carbohydrates with different digestion rates: a HFD containing rapid-digesting carbohydrates (OBE group) or slow-digesting carbohydrates (ISR group), for 4 weeks and the effect on the metabolism and signaling pathways were analyzed in different tissues. Animals from OBE group presented an overweight/obese phenotype with a higher body weight gain and greater accumulation of fat in adipose tissue and liver. This state was associated with an increase of HOMA index, serum diacylglycerols and triacylglycerides, insulin, leptin, and pro-inflammatory cytokines. In contrast, the change of carbohydrate profile in the diet to one based on slow digestible prevented the obesity-related adverse effects. In adipose tissue, GLUT4 was increased and UCPs and PPARg were decreased in ISR group respect to OBE group. In liver, GLUT2, FAS, and SRBP1 were lower in ISR group than OBE group. In muscle, an increase of glycogen, GLUT4, AMPK, and Akt were observed in comparison to OBE group. In conclusion, this study demonstrates that the replacement of rapidly digestible carbohydrates for slowly digestible carbohydrates within a highfat diet promoted a protective effect against the development of obesity and its associated comorbidities.Abbott Laboratories S.A

Programming Skeletal Muscle Metabolic Flexibility in Offspring of Male Rats in Response to Maternal Consumption of Slow Digesting Carbohydrates during Pregnancy

Skeletal muscle plays a relevant role in metabolic flexibility and fuel usage and the associated muscle metabolic inflexibility due to high-fat diets contributing to obesity and type 2 diabetes. Previous research from our group indicates that a high-fat and rapid-digesting carbohydrate diet during pregnancy promotes an excessive adipogenesis and also increases the risk of non-alcoholic fatty liver disease in the offspring. This effect can be counteracted by diets containing carbohydrates with similar glycemic load but lower digestion rates. To address the role of the skeletal muscle in these experimental settings, pregnant rats were fed high-fat diets containing carbohydrates with similar glycemic load but different digestion rates, a high fat containing rapid-digesting carbohydrates diet (HF/RD diet) or a high fat containing slow-digesting carbohydrates diet (HF/SD diet). After weaning, male offspring were fed a standard diet for 3 weeks (weaning) or 10 weeks (adolescence) and the impact of the maternal HF/RD and HF/SD diets on the metabolism, signaling pathways and muscle transcriptome was analyzed. The HF/SD offspring displayed better muscle features compared with the HF/RD group, showing a higher muscle mass, myosin content and differentiation markers that translated into a greater grip strength. In the HF/SD group, metabolic changes such as a higher expression of fatty acids (FAT/CD36) and glucose (GLUT4) transporters, an enhanced glycogen content, as well as changes in regulatory enzymes such as muscle pyruvate kinase and pyruvate dehydrogenase kinase 4 were found, supporting an increased muscle metabolic flexibility and improved muscle performance. The analysis of signaling pathways was consistent with a better insulin sensitivity in the muscle of the HF/SD group.This research was funded by European Union’s Seventh Framework Programme (FP7/2007–2013): project Early Nutrition, under grant agreement no. 289346