PPARγ as an indicator of vascular function in an experimental model of metabolic syndrome in rabbits

Abstract Background and aims Underlying mechanisms associated with vascular dysfunction in metabolic syndrome (MetS) remain unclear and can even vary from one vascular bed to another. Methods In this study, MetS was induced by a high-fat, high-sucrose diet, and after 28 weeks, aorta and renal arteries were removed and used for isometric recording of tension in organ baths, protein expression by Western blot, and histological analysis to assess the presence of atherosclerosis. Results MetS induced a mild hypertension, pre-diabetes, central obesity and dyslipidaemia. Our results indicated that MetS did not change the contractile response in either the aorta or renal artery. Conversely, vasodi…

Chronic exercise impairs nitric oxide pathway in rabbit carotid and femoral arteries

KEY POINTS: Some of the beneficial effects of exercise in preventing vascular related diseases are mediated by the enhancement of endothelial function where the role of nitric oxide (NO) is well documented, although the relevance of calcium activated potassium channels is not fully understood. The impact of oxidative stress induced by training on endothelial function remains to be clarified. By evaluating different endothelial vasodilator pathways on two vascular beds in a rabbit model of chronic exercise, we found a decreased NO bioavailability and endothelial nitric oxide synthase expression in both carotid and femoral arteries. Physical training induced carotid endothelial dysfunction as…

Relaxant and antiadrenergic effects of ranolazine in human saphenous vein.

Abstract OBJECTIVES Ranolazine improves vascular function in animal models. We evaluate the effects of ranolazine on vascular function and adrenergic response in human saphenous vein. METHODS Rings from 53 patients undergoing coronary artery bypass grafting were mounted in organ baths. Concentration–response curves to ranolazine were constructed in rings precontracted with phenylephrine, endothelin-1, vasopressin, KCl and the thromboxane A2 analogue U-46619. In rings precontracted with phenylephrine, relaxation to ranolazine was tested in the absence and presence of endothelial factors inhibitors, K+ channel blockers and verapamil. The effects of ranolazine on frequency–response and concent…

Efecto del entrenamiento físico sobre los factores endoteliales en el sistema arterial de conejo

Las enfermedades cardiovasculares constituyen una de las primeras causas de mortalidad en la población occidental y prácticamente el 50% se podrían prevenir con modificaciones del estilo de vida. En este sentido, la práctica regular de ejercicio físico se asocia con una reducción de entre un 20 a un 40% de la incidencia de eventos vasculares primarios y secundarios y del riesgo de muerte por enfermedad cardiovascular. Parte de estos beneficios estarían relacionados con los efectos directos y repetitivos que produce el ejercicio físico sobre la pared vascular, induciendo adaptaciones tanto funcionales como estructurales. Durante el ejercicio hay un aumento significativo del volumen minuto ca…

Anti-adrenergic effects of ranolazine in isolated rat aorta

Ranolazine, a piperazine derivative, is used as an anti- anginal drug to treat patients with chronic angina in clinical practice [1] and may improve coronary blood flow by reducing compression effects of ischemic contracture, and by improving endothelial function [2],[3]. In the present study we investigate the vascular effects of ranolazine on the endothelium, adrenergic system and Ca2+ in isolated rat aorta.

Effects of exercise training on adrenergic and cholinergic responses of rabbit carotid artery

Glucocorticoid receptor antagonism overcomes resistance to BRAF inhibition in BRAF(V600E)-mutated metastatic melanoma

Clinical applications of glucocorticoids (GC) in Oncology are dependent on their pro-apoptotic action to treat lymphoproliferative cancers, and to alleviate side effects induced by chemotherapy and/or radiotherapy. However, the mechanism(s) by which GC may also promote tumor progression remains unclear. GC receptor (GR) knockdown decreases the antioxidant protection of highly metastatic B16-F10 melanoma cells. We hypothesize that a GR antagonist (RU486, mifepristone) could increase the efficacy of BRAF-related therapy in BRAF(V600E)-mutated metastatic melanoma. In vivo formed spontaneous skin tumors were reinoculated into nude mice to expand the metastases of different human BRAF(V600E) mel…

Changes in Chemokines and Chemokine Receptors Expression in a Mouse Model of Alzheimer's Disease

The amyloid precursor protein plus presenilin-1 (APP/PS1) mice are a frequently-used model for Alzheimer's disease studies (AD). However, the data relevant to which proteins are involved in inflammatory mechanism are not sufficiently well-studied using the AD mouse model. Using behavioral studies, quantitative RT-PCR and Western-blot techniques, significant findings were determined by the expression of proteins involved in inflammation comparing APP/PS1 and Wild type mice. Increased GFAP expression could be associated with the elevation in number of reactive astrocytes. IL-3 is involved in inflammation and ABDF1 intervenes normally in the transport across cell membranes and both were found …

Efficacy and tolerability of EH301 for amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled human pilot study

Background: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by progressive loss of spinal and cortical motor neurons, leading to muscular atrophy, respiratory failure, and ultimately death. There is no known cure, and the clinical benefit of the two drugs approved to treat ALS remains unclear. Novel disease-modifying therapeutics that are able to modulate the disease course are desperately needed. Our objective was to evaluate the efficacy and tolerability of Elysium Health's candidate drug EH301 in people with ALS (PALS). Methods: This was a single-center, prospective, double-blind, randomized, placebo-controlled pilot study. Thirty-two PALS we…

Anti-inflammatory and antioxidant effects of ranolazine on primary cultured astrocytes

Because of its ability to block late INa [1], ranolazine is used as an antianginal agent for the treatment of chronic angina pectoris when angina is not adequately controlled by other agents [2]. Besides its cardiovascular effects, ranolazine improves different neuronal functions, and thus its use has been proposed for the treatment of pain and epileptic disorders [3,4]. Since astrocytes are involved in neuronal inflammatory processes, and autoimmune and neurodegenerative diseases [5], we have investigated the antiinflammatory and antioxidant effects of ranolazine in primary cultured astrocytes.

Neuronal effects of Sugammadex in combination with Rocuronium or Vecuronium.

Rocuronium (ROC) and Vecuronium (VEC) are the most currently used steroidal non-depolarizing neuromuscular blocking (MNB) agents. Sugammadex (SUG) rapidly reverses steroidal NMB agents after anaesthesia. The present study was conducted in order to evaluate neuronal effects of SUG alone and in combination with both ROC and VEC. Using MTT, CASP-3 activity and Western-blot we determined the toxicity of SUG, ROC or VEC in neurons in primary culture. SUG induces apoptosis/necrosis in neurons in primary culture and increases cytochrome C (CytC), apoptosis-inducing factor (AIF), Smac/Diablo and Caspase 3 (CASP-3) protein expression. Our results also demonstrated that both ROC and VEC prevent these…

Effects of Ranolazine on Astrocytes and Neurons in Primary Culture.

Ranolazine (Rn) is an antianginal agent used for the treatment of chronic angina pectoris when angina is not adequately controlled by other drugs. Rn also acts in the central nervous system and it has been proposed for the treatment of pain and epileptic disorders. Under the hypothesis that ranolazine could act as a neuroprotective drug, we studied its effects on astrocytes and neurons in primary culture. We incubated rat astrocytes and neurons in primary cultures for 24 hours with Rn (10-7, 10-6 and 10-5 M). Cell viability and proliferation were measured using trypan blue exclusion assay, MTT conversion assay and LDH release assay. Apoptosis was determined by Caspase 3 activity assay. The …

WIN 55,212-2, agonist of cannabinoid receptors, prevents amyloid β1-42 effects on astrocytes in primary culture

Alzheimer's disease (AD), a neurodegenerative illness involving synaptic dysfunction with extracellular accumulation of Aβ1-42 toxic peptide, glial activation, inflammatory response and oxidative stress, can lead to neuronal death. Endogenous cannabinoid system is implicated in physiological and physiopathological events in central nervous system (CNS), and changes in this system are related to many human diseases, including AD. However, studies on the effects of cannabinoids on astrocytes functions are scarce. In primary cultured astrocytes we studied cellular viability using MTT assay. Inflammatory and oxidative stress mediators were determined by ELISA and Western-blot techniques both in…

Efficacy and tolerability of EH301 for amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled human pilot study

Background: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by progressive loss of spinal and cortical motor neurons, leading to muscular atrophy, respiratory failure, and ultimately death. There is no known cure, and the clinical benefit of the two drugs approved to treat ALS remains unclear. Novel disease-modifying therapeutics that are able to modulate the disease course are desperately needed. Our objective was to evaluate the efficacy and tolerability of Elysium Health’s candidate drug EH301 in people with ALS (PALS). Methods: This was a single-center, prospective, double-blind, randomized, placebo-controlled pilot study. Thirty-two PALS we…