benzofurans and Metabolic-Diseases

Of the 415 million people suffering from diabetes worldwide, 90% have type 2 diabetes. Type 2 diabetes is characterized by hyperglycemia and occurs in obese individuals as a result of insulin resistance and inadequate insulin levels. Accordingly, diabetes drugs are tailored to enhance glucose disposal or target the pancreatic islet β cell to increase insulin secretion. The majority of the present-day insulin secretagogues, however, increase the risk of iatrogenic hypoglycemia, and hence alternatives are actively sought. The long-chain fatty acid, G protein-coupled receptor FFA1/Gpr40, is expressed in β cells, and its activation potentiates insulin secretion in a glucose-dependent manner. Preclinical data indicate that FFA1 agonism is an effective treatment to restore glucose homeostasis in rodent models of diabetes. This initial success prompted clinical trials in type 2 diabetes patients, the results of which were promising; however, the field suffered a significant setback when the lead compound TAK-875/fasiglifam was withdrawn from clinical development due to liver safety concerns. Nevertheless, recent developments have brought to light a surprising complexity of FFA1 agonist action, signaling diversity, and biological outcomes, raising hopes that with a greater understanding of the mechanisms at play the second round will be more successful.

Topics: Animals; Benzofurans; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Metabolic Diseases; Receptors, G-Protein-Coupled; Signal Transduction; Sulfones

Topics: Aspirin; Benzofurans; Chlorothiazide; Clinical Trials as Topic; Colchicine; Drug Combinations; Humans; Ketones; Kidney Diseases; Metabolic Diseases; Uric Acid

The lack of effective Alzheimer's disease treatment is becoming a challenge for researchers and prompts numerous attempts to search for and develop better therapeutic solutions. Compounds that affect several routes of the neurodegeneration cascade leading to the development of disease are of particular interest. An example of such substances is resveratrol and its synthetic and natural derivatives, which have gained popularity in recent years and show promise as a possible new therapeutic option in the approach to Alzheimer's disease treatment. In this article, the state of the art evidence on the role of resveratrol (RSV) in neuroprotection is presented; research results are summarized and the importance of resveratrol and its derivatives in the treatment of Alzheimer's disease are underlined. It also focuses on various modifications of the resveratrol molecule that should be taken into account in the design of future research on drugs against Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Benzofurans; Blood-Brain Barrier; Central Nervous System Diseases; Humans; Inflammation; Metabolic Diseases; Neuroprotection; Oxidative Stress; Resveratrol; Stilbenes; tau Proteins

Activating transcription factor 3 (Atf3) has been previously demonstrated to impact obesity and metabolism. However, a metabolic role of Atf3 in mice remains debatable. We investigated the role of Atf3 in mice and further investigated Atf3 expression as a therapeutic target for obesity and metabolic diseases. Atf3 knockout (KO) mice fed with a high fat diet (HFD) aggravated weight gain and impaired glucose metabolism compared to littermate control wild type (WT) mice. Atf3 KO aged mice fed with a chow diet (CD) for longer than 10 months also displayed increased body weight and fat mass compared to WT aged mice. We also assessed requirements of Atf3 in a phytochemical mediated anti-obese effect. Effect of sulfuretin, a previously known phytochemical Atf3 inducer, in counteracting weight gain and improving glucose tolerance was almost completely abolished in the absence of Atf3, indicating that Atf3 induction can be a molecular target for preventing obesity and metabolic diseases. We further identified other Atf3 small molecule inducers that exhibit inhibitory effects on lipid accumulation in adipocytes. These data highlight the role of Atf3 in obesity and further suggest the use of chemical Atf3 inducers for prevention of obesity and metabolic diseases.

Topics: Activating Transcription Factor 3; Aging; Animals; Anti-Obesity Agents; Benzofurans; Body Weight; Diet, High-Fat; Flavonoids; Glucose Intolerance; Metabolic Diseases; Mice, Knockout; Molecular Targeted Therapy; Obesity

Excess glucocorticoids promote visceral obesity and insulin resistance. The main regulator of intracellular glucocorticoid levels are 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive glucocorticoid into bioactive glucocorticoid such as cortisol in humans and corticosterone in rodents; therefore, the inhibition of 11β-HSD1 has considerable therapeutic potential for metabolic diseases including obesity and diabetes. Benzofuran is a key structure in many biologically active compounds such as benzbromarone, malibatol A and (+)-liphagal. The aim of this study was to investigate the inhibitory effect of benzofuran derivatives on 11β-HSD1 in mesenteric adipose tissue from rodents. 11β-HSD1 activity was determined by incubation of rat mesenteric adipose tissue microsomes in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH) with and without benzofuran derivatives (Compounds 1-14). The corticosterone produced was measured by HPLC. More than 40% of 11β-HSD1 inhibition was observed in Compounds 1, 5, 7 and 8. Moreover, Compounds 7 and 8 inhibited the 11β-HSD1 activity in adipose microsomes dose- and time-dependently, as well as in 3T3-L1 adipocytes. Compounds 7 and 8 did not inhibit 11β-HSD type 2 (11β-HSD2), whereas Compounds 1 and 5 inhibited 11β-HSD2 by 18.7% and 56.3%, respectively. Further, a kinetic study revealed that Compounds 7 and 8 acted as non-competitive inhibitors of 11β-HSD1. Ki (nmol/h/mg protein) values of Compounds 7 and 8 were 17.5 and 24.0, respectively, with IC50 (µM) of 10.2 and 25.6, respectively. These data indicate that Compounds 7 and 8 are convincing candidates for seed compounds as specific inhibitors of 11β-HSD1 and have the potential to be developed as anti-obesity drugs.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; 3T3-L1 Cells; Animals; Benzofurans; Corticosterone; Dose-Response Relationship, Drug; Intra-Abdominal Fat; Male; Mesentery; Metabolic Diseases; Mice; Microsomes; NADP; Obesity; Rats; Rats, Wistar

Topics: Adult; Allopurinol; Benzoates; Benzofurans; Bromine; Gout; Gout Suppressants; Humans; Male; Metabolic Diseases; Uric Acid

Topics: Antihypertensive Agents; Antimalarials; Arsenic; Benzofurans; Drug-Related Side Effects and Adverse Reactions; Gold; Humans; Metabolic Diseases; Pharmaceutical Preparations; Phenothiazines; Phosphates; Silver; Thorium Dioxide

Topics: Benzofurans; Cornea; Eye; Eye Diseases; Face; Humans; Iodine Isotopes; Lacrimal Apparatus; Male; Metabolic Diseases; Middle Aged; Myocardium; Neck; Pigmentation Disorders; Radionuclide Imaging

Topics: Adult; Angina Pectoris; Benzofurans; Coronary Disease; Eye Diseases; Humans; Metabolic Diseases; Middle Aged

Topics: Aged; Angina Pectoris; Benzofurans; Cornea; Coronary Disease; Eye Diseases; Female; Humans; Metabolic Diseases

Topics: Benzofurans; Chloroquine; Cornea; Corneal Dystrophies, Hereditary; Eye Diseases; Glycolipids; Humans; Lipid Metabolism, Inborn Errors; Metabolic Diseases