Akt Regulates TNFα synthesis downstream of RIP1 kinase activation during necroptosis.

Necroptosis is a regulated form of necrotic cell death that has been implicated in the pathogenesis of various diseases including intestinal inflammation and systemic inflammatory response syndrome (SIRS). In this work, we investigated the signaling mechanisms controlled by the necroptosis mediator receptor interacting protein-1 (RIP1) kinase. We show that Akt kinase activity is critical for necroptosis in L929 cells and plays a key role in TNFα production.

A HPLC method for the quantitative determination of N-(2-hydroxy-5-nitrophenylcarbamothioyl)-3,5-dimethylbenzamide in biological samples.

A sensitive and simple HPLC method was developed for the determination of a novel compound, a potential anti-cancer drug, N-(2-hydroxy-5-nitrophenylcarbamothioyl)-3,5-dimethylbenzamide (DM-PIT-1), a member of the new structural class of non-phosphoinositide small molecule antagonist of phosphatidylinositol-3,4,5-trisphosphate-pleckstrin-homology domain interactions, in mouse plasma and tumor tissue homogenates. The chromatographic separation of DM-PIT-1 was achieved on C18 column using isocratic elution with acetonitrile-water (70:30) containing 0.1% formic acid (v/v).

Small molecule inhibition of phosphatidylinositol-3,4,5-triphosphate (PIP3) binding to pleckstrin homology domains.

The PI3-kinase (PI3K) pathway regulates many cellular processes, especially cell metabolism, cell survival, and apoptosis. Phosphatidylinositol-3,4,5-trisphosphate (PIP3), the product of PI3K activity and a key signaling molecule, acts by recruiting pleckstrin-homology (PH) domain-containing proteins to cell membranes. Here, we describe a new structural class of nonphosphoinositide small molecule antagonists (PITenins, PITs) of PIP3-PH domain interactions (IC(50) ranges from 13.

In vitro cytotoxicity of novel pro-apoptotic agent DM-PIT-1 in PEG-PE-based micelles alone and in combination with TRAIL.

The purpose of this study was to develope and characterize a micellar formulations of N-{[(2-hydroxy-5- nitrophenyl)amino]carbonothioyl}-3,5-dimethylbenzamide (DM-PIT-1)-a new small molecule non-lipid antagonist of phopshotidylinositol-3.4.5-triphopshate and inhibitor of the PI3-kinase pathway.

Photodynamic therapy of experimental B-16 melanoma in mice with tumor-targeted 5,10,15,20-tetraphenylporphin-loaded PEG-PE micelles.

Polyethylene glycol (PEG)-diacyl lipid micelles have been prepared by loading with the hydrophobic meso-5,10,15,20-tetraphenyl-21H,23H-porphine (TPP) and used for the photodynamic treatment of B-16 melanoma cells in vitro and in vivo. The use of PEG-PE micelles allowed for a 150-fold increased the solubilization of TPP, compared with the native drug. The average size of the PEG-PE micelles was in the range of 10-12 nm with a narrow size distribution.

Chemotherapy of glioblastoma in rats using doxorubicin-loaded nanoparticles.

Glioblastomas belong to the most aggressive human cancers with short survival times. Due to the blood-brain barrier, they are mostly inaccessible to traditional chemotherapy. We have recently shown that doxorubicin bound to polysorbate-coated nanoparticles crossed the intact blood-brain barrier, thus reaching therapeutic concentrations in the brain.