oxadiazoles and Vascular-Diseases

A series of furoxan-based nitric oxide-releasing chrysin derivatives were synthesized. Pharmacological assays indicated that all chrysin derivatives exhibited in vitro inhibitory activities against aldose reductase and advanced glycation end-product formation. Some chrysin derivatives were also found to increase the glucose consumption of HepG2 cells. Furthermore, the compounds released a low amount of NO in the presence of L-cysteine (range from 0.20% to 1.89%). These hybrid furoxan-based NO donor chrysin derivatives offer a mutual prodrug design concept for the development of therapeutic or preventive agents for vascular complications due to diabetes.

Topics: Aldehyde Reductase; Cysteine; Flavonoids; Glycation End Products, Advanced; Hep G2 Cells; Humans; Nitric Oxide; Oxadiazoles; Vascular Diseases

Sphingosine 1-phosphate (S1P) is a key endogenous regulator of the response to lung injury, maintaining endothelial barrier integrity through interaction with one of its receptors, S1P(1). The short-term administration of S1P or S1P(1) receptor agonists enhances endothelial monolayer barrier function in vitro, and attenuates injury-induced vascular leak in the lung and other organ systems in vivo. Although S1P(1) agonists bind to and activate S1P(1), several of these agents also induce receptor internalization and degradation, and may therefore act as functional antagonists of S1P(1) after extended exposure. Here we report on the effects of prolonged exposure to these agents in bleomycin-induced lung injury. We demonstrate that repeated administration of S1P(1) agonists dramatically worsened lung injury after bleomycin challenge, as manifested by increased vascular leak and mortality. Consistent with these results, prolonged exposure to S1P(1) agonists in vitro eliminated the ability of endothelial cell monolayers to respond appropriately to the barrier-protective effects of S1P, indicating a loss of normal S1P-S1P(1) signaling. As bleomycin-induced lung injury progressed, continued exposure to S1P(1) agonists also resulted in increased pulmonary fibrosis. These data indicate that S1P(1) agonists can act as functional antagonists of S1P(1) on endothelial cells in vivo, which should be considered in developing these agents as therapies for vascular leak syndromes. Our findings also support the hypothesis that vascular leak is an important component of the fibrogenic response to lung injury, and suggest that targeting the S1P-S1P(1) pathway may also be an effective therapeutic strategy for fibrotic lung diseases.

Topics: Animals; beta-Alanine; Bleomycin; Blood Coagulation; Endothelial Cells; Fibrosis; Fingolimod Hydrochloride; Humans; Lung Injury; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Oxadiazoles; Pneumonia; Propylene Glycols; Pulmonary Alveoli; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine; Survival Analysis; Thiophenes; Vascular Diseases

Topics: Butylamines; Drug Tolerance; Ethylamines; Humans; Ischemia; Otorhinolaryngologic Diseases; Oxadiazoles; Vascular Diseases; Vasodilator Agents

Topics: Animals; Arteries; Butylamines; Diabetic Angiopathies; Dogs; Drug Evaluation; Ethylamines; Humans; Leg; Oxadiazoles; Rats; Regional Blood Flow; Vascular Diseases; Vasodilator Agents

Topics: Aged; Arteries; Butylamines; Ethylamines; Humans; Leg; Male; Middle Aged; Oxadiazoles; Vascular Diseases

Topics: Adult; Aged; Angina Pectoris; Biliary Dyskinesia; Esophageal Achalasia; Female; Gastrointestinal Diseases; Gastrointestinal Motility; Humans; Male; Middle Aged; Muscle Cramp; Oxadiazoles; Pyloric Stenosis; Vascular Diseases; Vomiting

Topics: Adult; Aged; Antihypertensive Agents; Arteriosclerosis Obliterans; Blood Circulation; Cerebrovascular Circulation; Diabetic Angiopathies; Female; Humans; Hypertension; Intracranial Arteriosclerosis; Male; Middle Aged; Oxadiazoles; Papaverine; Plethysmography, Impedance; Quinolines; Thromboangiitis Obliterans; Vascular Diseases