ABSTRACT
Interleukin-12 (IL-12) and IL-23 are proinflammatory cytokines and therapeutic targets for inflammatory and autoimmune diseases, including inflammatory bowel diseases, psoriasis, rheumatoid arthritis, and multiple sclerosis. We describe the discovery of APY0201, a unique small molecular IL-12/23 production inhibitor, from activated macrophages and monocytes, and demonstrate ameliorated inflammation in an experimental model of colitis. Through a chemical proteomics approach using a highly sensitive direct nanoflow LC-MS/MS system and bait compounds equipped with the FLAG epitope associated regulator of PIKfyve (ArPIKfyve) was detected. Further study identified its associated protein phosphoinositide kinase, FYVE finger-containing (PIKfyve), as the target protein of APY0201, which was characterized as a potent, highly selective, ATP-competitive PIKfyve inhibitor that interrupts the conversion of phosphatidylinositol 3-phosphate (PtdIns3P) to PtdIns(3,5)P2. These results elucidate the function of PIKfyve kinase in the IL-12/23 production pathway and in IL-12/23-driven inflammatory disease pathologies to provide a compelling rationale for targeting PIKfyve kinase in inflammatory and autoimmune diseases.
Subject(s)
Interleukin-12/antagonists & inhibitors , Interleukin-23/antagonists & inhibitors , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Small Molecule Libraries/pharmacology , Animals , Cell Line , Colitis/drug therapy , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Discovery , Female , Humans , Inflammation/drug therapy , Interleukin-10/deficiency , Leukocytes, Mononuclear/drug effects , Macrophages/drug effects , Mice , Mice, Inbred BALB C , Mice, Knockout , Mice, SCID , Models, Molecular , Molecular Structure , Pyrazoles/chemistry , Pyrimidines/chemistry , Small Molecule Libraries/chemistry , Structure-Activity RelationshipABSTRACT
Metabolic syndrome (MetS) has been redefined by a new criterion in Japan, in which waist circumference cut-off points, that is 85 cm for men and 90 cm for women, are used; however, objections are rising against this criterion. The present study examined the criterion for waist circumference to predict the accumulation of the components of MetS. In the present study, we used data for 5972 Japanese people who received annual health examinations, and 621 men (16.3%) and 51 women (2.4%) were diagnosed as having MetS. A cut-off point as a predictor for two or more components of MetS was evaluated by the sensitivity/specificity and a receiver operating characteristic analysis. The optimal point of waist circumference was estimated as being approximately 84 cm for men and 80 cm for women. We therefore recommend revising the cut-off value for the criterion of MetS in women according to our results and studies from other investigators. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00020.x, 2010).
ABSTRACT
An enantioselective total synthesis of both enantiomers of caryophyllene-type sesquiterpenoid pestalotiopsin A has been achieved, thereby establishing the absolute stereochemistry of natural (+)-pestalotiopsin A. Highlights of the synthesis include a [2 + 2] cycloaddition of N-propioloyl Oppolzer's camphorsultam and ketene dialkyl acetal and subsequent highly stereoselective 1,4-hydride addition/protonation, an aldol reaction of functionalized bicyclic lactone with aldehyde, an efficient intramolecular Nozaki-Hiyama-Kishi (NHK) reaction for the construction of the highly strained (E)-cyclononene ring, and a palladium-catalyzed reduction of allylic mesylate with retention of the E configuration.
