A New Series of Orally Bioavailable Chemokine Receptor 9 (CCR9) Antagonists; Possible Agents for the Treatment of Inflammatory Bowel Disease.

Chemokine receptor 9 (CCR9), a cell surface chemokine receptor which belongs to the G protein-coupled receptor, 7-trans-membrane superfamily, is expressed on lymphocytes in the circulation and is the key chemokine receptor that enables these cells to target the intestine. It has been proposed that CCR9 antagonism represents a means to prevent the aberrant immune response of inflammatory bowel disease in a localized and disease specific manner and one which is accessible to small molecule approaches. One possible reason why clinical studies with vercirnon, a prototype CCR9 antagonist, were not successful may be due to a relatively poor pharmacokinetic (PK) profile for the molecule.

Effect of premortem and postmortem factors on the distribution and preservation of antioxidant activities in the cytosol and synaptosomes of human brains.

The human brain displays oxidant and antioxidant markers with regional specificity that directly impinges on neuronal function in aging and in disease states. Similarly, the antioxidant activities might exhibit differential intracellular distribution rendering subcellular structures differentially vulnerable to toxic insults. To investigate the subcellular distribution of antioxidant activities in the human postmortem brain, we assayed superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST) in the cytosol and synaptosomal fraction from the frontal cortex (FC) of 45 postmortem human brains.

Elevated oxidative stress and decreased antioxidant function in the human hippocampus and frontal cortex with increasing age: implications for neurodegeneration in Alzheimer's disease.

Oxidative stress and mitochondrial damage are implicated in the evolution of neurodegenerative diseases. Increased oxidative damage in specific brain regions during aging might render the brain susceptible to degeneration. Previously, we demonstrated increased oxidative damage and lowered antioxidant function in substantia nigra during aging making it vulnerable to degeneration associated with Parkinson's disease.

Effect of storage time, postmortem interval, agonal state, and gender on the postmortem preservation of glial fibrillary acidic protein and oxidatively damaged proteins in human brains.

Biochemical analyses of many brain diseases have highlighted that oxidative damage of proteins and astrogliosis are important events associated with pathology. However, human studies on the status of protein oxidation/nitration and astrogliosis [indicated by expression of glial fibrillary acidic protein (GFAP)] heavily depend on postmortem tissues that might be altered by pre and postmortem factors. To evaluate the effect of these variables, we tested whether the status of GFAP expression, oxidized proteins, and nitrated proteins (by protein 3-nitrotyrosine or 3-NT) were affected in postmortem human brains (n=48) by increased storage time (11.