Effects of 1-methyltryptophan stereoisomers on IDO2 enzyme activity and IDO2-mediated arrest of human T cell proliferation

IDO2 is a newly discovered enzyme with 43?% similarity to classical IDO (IDO1) protein and shares the same critical catalytic residues. IDO1 catalyzes the initial and rate-limiting step in the degradation of tryptophan and is a key enzyme in mediating tumor immune tolerance via arrest of T cell proliferation. The role of IDO2 in human T cell immunity remains controversial. Here, we demonstrate that similar to IDO1, IDO2 also degrades tryptophan into kynurenine and is inhibited more efficiently by Levo-1-methyl tryptophan (L-1MT), an IDO1 competitive inhibitor, than by dextro-methyl tryptophan (D-1MT). Although IDO2 enzyme activity is weaker than IDO1, it is less sensitive to 1-MT inhibition than IDO1. Moreover, our results indicate that human CD4⁺ and CD8⁺ T cell proliferation was inhibited by IDO2, but both L-1MT and D-1MT could not reverse IDO2-mediated arrest of cell proliferation, even at high concentrations. These data indicate that IDO2 is an inhibitory mechanism in human T cell proliferation and support efforts to develop more effective IDO1 and IDO2 inhibitors in order to overcome IDO-mediated immune tolerance.     

Acetate causes renoprotection like androgen and mineralocorticoid receptors blockade in testosterone-exposed pregnant rats

Molecular and Cellular Biochemistry - The kidney plays a critical role in human health and deviation from its normal function can lead to severe morbidity and mortality. Exposure to excess...     

Compaction characteristics of ethylcellulose in the presence of some channeling agents: Technical note

Summary and Conclusion  This study investigated the effect of some commonly used release enhancers on the compaction characteristics of EC. The wet granulation method of massing and screening was used, and compacts were produced by compressing granules for 60 seconds at various compression pressures. The Heckel equation, used for the analysis of results, showed that EC alone showed better compressibility than formulations with additives. The hygroscopic additives, sorbitol and PEG 4000, produced unusual Heckel plots, while the nonhygroscopic additives, PEG 10 000 and mannitol, produced biphasic Heckel plots. The results also indicate that EC alone exhibited the highest degree of packing in the die, with the addition of mannitol reducing the extent of packing the most. The presence of additives in EC for-mulations increased the pressures at which plastic deformation of EC granules occurred. The extent of this depended on the type of additive, with mannitol imparting the highest resistance to deformation of EC granules and sorbitol the lowest. It can be concluded that additives such as PEG 4000, PEG 10 000, sorbitol, and mannitol, which are often used as channeling agents in sustained-release formulations containing hydrophobic matrix formers, affect the deformation characteristics of EC, with the extent and nature of the effect dependent on the nature of the additive. Published: July 14, 2006