University of California

Other

Edward A Dennis

George Kokotos

Violetta Constantinou-Kokotou

William N Washburn

Oswald Quehenberger

Rohit Loomba

Samuel David

Aaron Armando

Tony L Yaksh

Lin Yu

Aijun Wang

Efrosini Barbayianni

Ruben Lopez-Vales

Victoria Magrioti

Daren Stephens

Athena Kalyvas

Karin Killermann Lucas

Camilla Svensson

David A Six

Laure J Reynolds

The disclosure provides methods for differentiating between non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. The method includes measuring eicosanoids and fatty acid levels in a biological sample.

Methods and compositions for identifying non-alcoholic fatty liver disease

The disclosure relates to the substantially non-invasive diagnosis of liver disease, especially to enable intervention in the progression of such disease at an early stage. This invention further relates to the use of plasma biomarkers to differentiate nonalcoholic steatohepatitis (NASH) from nonalcoholic fatty liver (NAFL) and non-nonalcoholic fatty liver disease (NAFLD), and normal controls. Specifically, the invention relates to the use of free eicosanoids and other polyunsaturated fatty acid (PUFA) metabolite levels in plasma to differentiate NASH from NAFL and non-NAFLD normal controls.

Differential diagnosis of liver disease

The present invention relates to the substantially non-invasive diagnosis of liver disease, especially to enable intervention in the progression of such disease at an early stage. This invention further relates to the use of plasma biomarkers to differentiate nonalcoholic steatohepatitis (NASH) from nonalcoholic fatty liver (NAFL) and non-nonalcoholic fatty liver disease (NAFLD), and normal controls. Specifically, the invention relates to the use of free eicosanoids and other polyunsaturated fatty acid (PUFA) metabolite levels in plasma to differentiate NASH from NAFL and non-NAFLD normal controls.

Methods and compounds useful for inhibiting a phoshpolipase Aare provided, the methods comprising contacting the phoshpolipase Awith a compound having the structure A, or pharmaceutically acceptable salts thereof: wherein Ris H, F, NH, or COOH; Ris, H, linear saturated or unsaturated alkyl, alkenyl, or alkynyl; each of Rand Ris independently H, linear saturated or unsaturated alkyl, alkenyl, alkynyl, phenyl, or substituted phenyl; Ris H, (C-C) alkyl such as methyl or ethyl; X is aryl or substituted aryl, such as phenyl or a substituted phenyl; and Y is O or S. 

Amides as inhibitors of human secreted phospholipase A2

The disclosure provides a series of 2-oxoamides based on dipeptides and pseudodipeptides, which were synthesized and their activities toward two human intracellular phospholipases A2 (GIVA CPLA 2 and GVIA 1PLA 2) and one human secretory phospholipase A2 (GV sPLA 2) were evaluated. Derivatives containing a free carboxyl group are selective GIVA cPLA 2 inhibitors. A derivative based on the ethyl ester of an ether pseudodipeptide is the first 2-oxoamide, which preferentially inhibits GVIA iPLA 2. The effect of 2-oxoamides on the generation of arachidonic acid from RAW 264.7 macrophages was also studied. It was found that selective GIVA cPLA 2 inhibitors preferentially inhibited cellular arachidonic acid release; in which one pseudodipeptide gave an IC50 value of 2 &#x3bc;M.

2-oxamide inhibitors of phospholipase A2 activity and cellular arachidonate release based on dipeptides and pseudopeptides

Phospholipase A(PLA) forms are expressed in spinal cord whose inhibition induces a potent antihyperalgesia. PLAinhibitor compounds are provided that include a common motif consisting of a 2-oxoamide with a hydrocarbon tail and a four carbon tether. The compounds block Group IVA calcium dependent PLA(cPLA) and/or Group VIA calcium independent PLA(iPLA) and/or Group V secreted PLA(sPLA). Pharmaceutical compositions of compounds having cPLAinhibitory activity (but not iPLAor sPLAinhibitory activity) are useful in treating multiple sclerosis, while compositions of compounds having sPLAinhibitory activity (as well as iPLAand CPLAactivity) are useful in treating spinal cord injuries (with related functional recovery).

Phospholipase A2 inhibitors and their use in treating neurological injury and disease

Specific, highly potent 2-oxo-amide based inhibitors of phospholipase A(PLA) activity are provided. A role for PLAactivity in spinally mediated inflammatory processes is established, and a method for treating hyperalgesia and other inflammatory conditions associated with PLAactivity is provided.

Compositions and methods for inhibition of phospholipase A2 mediated inflammation

A cloned of a human brain lysophospholipid-specific lysophospholipase enzyme molecule, its potential use for treatment of a host of diseases and method of inactivation are disclosed. Also disclosed are its distribution in tissue sand detailed kinetic analysis. hLysoPLA has a single substrate binding site and a surface recognition site. In contrast to many nonspecific lipolytic enzymes that exhibit lysophospholipase activity, hLysoPLA hydrolyzes only lysophospholipids and has no other significant enzymatic activity.

Cloned human lysophospholipase

The present invention provides compounds that function as hydrolytic enzyme inhibitors (inactivators) and substrates. These compounds are useful in assays to detect and measure levels of hydrolytic enzyme activity and are more particularly useful in treatment regimens for various disease states and conditions implicating the underlying specific hydrolytic enzyme. Examples of hydrolytic enzymes include, but are not limited to, phospholipases, lipases, esterases, proteases, etc.

Hydrolytic enzyme inhibitors/inactivators and methods for using same

A non-radioactive, spectrophotometric, microtiter plate assay for human cystolic phospholipase A.sub.2 (cPLA.sub.2) is described. The assay utilizes a novel synthetic thiol-phospholipid analog as a substrate. In one embodiment, the substrate is a phosphatidylcholine derivative with an arachidonoylthioester in the sn-2 position and an alkenyl-ether or alkenyl-ether in the sn-1 position. The alkyl-ether and the alkenyl-ether in the sn-1 position of the substrate ensures that the assay will only measure cPLA.sub.2 activity and will not be complicated by metabolism of the lysophospholipid product by the enzyme's and lysophospholypase activity.

Assay and substrate for arachidonoyl-specific phospholipase A2

The present invention provides prodrugs that serve as useful therapeutics for various disease states and conditions mediated by underlying specific hydrolytic enzyme activity. The prodrugs hereof (additionally) impart a physiologically bioactive component thus providing prodrug compounds that are capable of imparting dual effect systemically.

Growing community of inventors

La Jolla, CA, United States of America

Edward A Dennis