Abstract: Methods of treating a metabolic disorder comprising orally administering to the patient a small molecule inhibitor of plasminogen activator inhibitor 1 (PAI-1) are described. The treatment with the PAI-1 inhibitor changes at least one metabolic measurement of the patient such as fasting glucose, fasting plasma insulin and fasting plasma LDL when compared to the metabolic measurement of the patient in an untreated condition. The metabolic disorder treated by the methods may include obesity, type 2 diabetes mellitus, nonalcoholic fatty liver disease, non-alcoholic steatohepatitis, hyperlipidemia, metabolic syndrome, and cardiovascular disease, hypercholesterolemia, familial hypercholesterolemia, or elevated LDL.

Abstract: The present invention provides compositions, systems, and methods for treating a condition characterized by elevated Fibroblast Growth Factor 23 (FGF23) with a composition comprising: i) an agent that causes an increase in expression of urokinase plasminogen activator (uPA) and/or tissue plasminogen activator (tPA), ii) purified uPA, and/or purified tPA.

Abstract: The present invention provides compositions, systems, and methods for treating a condition characterized by elevated Fibroblast Growth Factor 23 (FGF23) with a composition comprising: i) an agent that causes an increase in expression of urokinase plasminogen activator (uPA) and/or tissue plasminogen activator (tPA), ii) purified uPA, and/or purified tPA.

Abstract: The invention relates to methods, compositions, and kits for combination therapy of diabetes and diabetes-related diseases and conditions (e.g., obesity). The invention finds use in patients suffering from or at risk for diabetes or diabetes-related conditions generally, and in patients also suffering from or at risk for fluid retention (e.g., edema, congestive heart failure) and/or in need of synergistic anti-inflammatory, anti-hypertensive, and anti-diabetic effect.

Abstract: Intracoronary delivery of endothelial progenitor cells (EPCs) is an emerging concept for the treatment of cardiovascular disease, and enhancement of EPC adhesion to vascular endothelium should improve cell retention within targeted organs, as well as vascular development. The present inventors have shown that stimulation of adenosine receptors (AdoR) in murine embryonic EPCs (eEPCs) and cardiac endothelial cells (cECs) rapidly, within minutes, increased eEPC adhesion to cECs. eEPCs and cECs were found to predominantly express functional A1 and A2B AdoR subtypes, respectively, and both subtypes are involved in the regulation of eEPC adhesion to cECs. Adenosine, adenosine precursors (e.g., AMP) and adenosine receptor agonists thus can be used to stimulate EPC/stem cell homing and engraftment in cell-based therapies.

Abstract: A method of testing a candidate composition for PAI-1 inhibition activity is disclosed. The method includes the steps of obtaining a transgenic non-human warm blooded vertebrate animal having incorporated into its genome a PAI-1 gene encoding a biologically active PAI-1 polypeptide, the PAI-1 gene being present in the genome in a copy number effective to confer over-expression in the transgenic non-human animal of the PAI-1 polypeptide; administering the composition to the transgenic non-human animal; and observing the transgenic non-human animal for determination of a change in the transgenic non-human animal indicative of inhibition of the activity of PAI-1. A transgenic non-human animal useful in such a method is also disclosed, as is a PAI-1 transgene construct encoding a biologically active PAI-1 polypeptide useful for preparing the transgenic non-human animal.

Abstract: A method of treating a warm-blooded vertebrate animal having a medical condition in need of treatment with a composition that exhibits PAI-1 inhibition activity is disclosed. The method includes the steps of administering a treatment effective amount of the composition to a warm-blooded vertebrate animal having a medical condition selected from the group consisting of alopecia, undesired weight loss, Alzheimer's Disease, systemic amyloidosis, myelofibrosis, male pattern baldness, glomerulosclerosis, and combinations thereof; and observing an improvement in the medical condition in the warm-blooded vertebrate animal having the medical condition. A method of testing a candidate composition for PAI-1 inhibition activity is also disclosed.

Abstract: A method for preventing or reducing a risk of cardiovascular disease in a healthy subject via administration of an ACE inhibitor. Also provided is a method for reducing a plasma level of PAI-1 in a healthy subject via administration of an ACE inhibitor. The methods can be combined with hormone replacement therapy for improved effectiveness. Representative healthy subjects include post-menopausal women.

Abstract: Angiotensin IV (VAL-TYR-ILE-HIS-PRO-PHE), a degradation product of angiotensin II previously thought to be inactive, interacts directly with endothelial cells to induce expression of PAI-1 and thereby to inhibit clot lysis attributable to endogenous t-PA. Moreover, angiotensin IV does not effect substantial physiological changes (vasoconstriction, increased blood pressure, etc.) characteristic of angiotensin II. Fibrinolysis is promoted by reducing the amount or the effect of angiotensin IV. Fibrinolysis is inhibited by providing enhanced angiotensin IV. Methods of screening candidates for antagonizing angiotensin IV are also disclosed.