digoxin and Metabolic-Syndrome

Heart failure remains a major health problem in the United States, affecting 5.8 million Americans. Its prevalence continues to rise due to the improved survival of patients. Despite advances in treatment, morbidity and mortality remain very high, with a median survival of about 5 years after the first clinical symptoms. This article describes the causes, classification, and management goals of heart failure in Stages A and B.

Topics: Adrenergic beta-Antagonists; Alcohol Drinking; Angiotensin-Converting Enzyme Inhibitors; Cardiac Pacing, Artificial; Cardiotonic Agents; Cardiotoxins; Coronary Artery Disease; Defibrillators, Implantable; Diabetic Cardiomyopathies; Digoxin; Dyslipidemias; Early Diagnosis; Endocrine System Diseases; Heart Failure; HIV Infections; Humans; Hypertension; Metabolic Syndrome; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic; Risk Factors; Sedentary Behavior; Sleep Apnea Syndromes; Smoking; Tachycardia

Drugs that mirror the cellular effects of starvation mimics are considered promising therapeutics for common metabolic disorders, such as obesity, liver steatosis, and for ageing. Starvation, or caloric restriction, is known to activate the transcription factor EB (TFEB), a master regulator of lipid metabolism and lysosomal biogenesis and function. Here, we report a nanotechnology-enabled high-throughput screen to identify small-molecule agonists of TFEB and discover three novel compounds that promote autophagolysosomal activity. The three lead compounds include the clinically approved drug, digoxin; the marine-derived natural product, ikarugamycin; and the synthetic compound, alexidine dihydrochloride, which is known to act on a mitochondrial target. Mode of action studies reveal that these compounds activate TFEB via three distinct Ca

Topics: Animals; Autophagosomes; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Biguanides; Caenorhabditis elegans; Calcium; Caloric Restriction; Diet, High-Fat; Digoxin; Enzyme Inhibitors; Fatty Liver; HeLa Cells; High-Throughput Screening Assays; Humans; Lactams; Lipid Metabolism; Liver; Longevity; Lysosomes; Metabolic Syndrome; Mice; Mitochondria; Starvation

Metabolic syndrome (MetS) is a health disorder that increases the risk for cardiovascular complications such as heart disease and type 2 diabetes. Some drugs used in patients with MetS are substrates of intestinal P-glycoprotein (P-gp), one of the most important efflux pumps that limit the absorption of xenobiotics. Thus, their bioavailability could be affected by changes in this transporter. Because one of the major causes of MetS in humans is excessive sugar intake, the aim of this study was to evaluate the effect of a fructose-rich diet on intestinal P-gp activity and protein expression in male Sprague-Dawley rats.. Fructose-drinking animals received standard chow and 15% (w/v) fructose in the drinking water over 8 wk; control rats were fed on standard chow and tap water.. Ileal protein expression of P-gp was 50% lower in fructose-drinking rats than in control animals. This reduction was confirmed by immunofluorescence microscopy. These results correlated well with the decrease of about 50% in the transport rate of the substrate rhodamine 123 in everted intestinal sacs. Finally, an increase of 62% in the intestinal absorption of digoxin, a P-gp substrate used as therapeutic drug, was observed in vivo, in fructose-drinking animals.. The present study demonstrated that MetS-like conditions generated by enhanced fructose intake in rats decreased the protein expression and activity of ileal P-gp, thus increasing the bioavailability of P-gp substrates.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Availability; Dietary Carbohydrates; Digoxin; Enzyme Inhibitors; Fructose; Ileum; Intestinal Absorption; Intestinal Mucosa; Male; Membrane Transport Proteins; Metabolic Syndrome; Rats, Sprague-Dawley; Rhodamine 123