Search

Hepatocyte growth factor (HGF), through activation of the c‐MET receptor, mediates biological processes critical for tissue regeneration; however, its clinical application is limited by protein instability and poor recombinant expression. We previously engineered an HGF fragment (eNK1) that possesses increased stability and expression yield and developed a c‐MET agonist by coupling eNK1 through an introduced cysteine residue. Here, we further characterize this eNK1 dimer and show it elicits significantly greater c‐MET activation, cell migration, and proliferation than the eNK1 monomer. The efficacy of the eNK1 dimer was similar to HGF, suggesting its promise as a c‐MET agonist.HGF is difficult to produce and unstable, highlighting a need for c‐MET agonists. A disulfide‐linked dimer (eNK1 dimer) was created from an engineered HGF fragment. The eNK1 monomer is a weak agonist and only activates c‐MET at high concentrations. The eNK1 dimer is a potent activator of c‐MET, cell migration, and proliferation. The eNK1 dimer elicits similar biological activity compared to HGF. [ABSTRACT FROM AUTHOR]

The solution structure of the Y1 receptor agonist, porcine [Leu31, Pro34]NPY, has been investigated by two-dimensional NMR and molecular modeling. A complete assignment of the NMR resonances was achieved and 201 inter-residue nuclear Overhauser enhancement spectroscopy (NOESY) connectivities could be identified, comprising several connectivities between the N- and C-terminal segments. A molecular model was calculated by distance geometry, simulated annealing and conjugate gradients energy minimization using the NOE constraints. The results indicate that, like NPY and other peptides of the family, [Leu31, Pro34]NPY adopts a folded hairpin structure with the terminal segments in close proximity. Analysis of the secondary chemical shifts for the CHα's and of the temperature dependence of the NH chemical shifts combined with the NOE constraints indicates a tendency toward helix structure for the segment 18-30 and the presence of turn structure for the C-terminal segment (residues 31-36). Native NPY and [Leu31, Pro34]NPY have most of their structures in common but differ slightly in their C-terminal portion. Based on the structures of NPY and of its specific agonists, [Leu31, Pro34]NPY and NPY 13-36, conclusions can be drawn about the structural requirements for binding to the Y1 and Y2 receptor subtypes. [ABSTRACT FROM AUTHOR]

The article focuses on a study conducted to analyze the impact of single-dose of astemizole in children, which found that a single dose of astemizole would suppress the histamine-induced wheal in children. It is noted that in a predetermined sequence of sites on the volar surface of the forearm pre-dose, epicutaneous tests with histamine phosphate solution, 1 mg/mL and 10 mg/mL were performed.

Neutrophils from patients with localized juvenile periodontitis (LJP) show several functional abnormalities. Recently, it has become increasingly apparent that the reason for these changes lies in part at the post receptor level of cellular metabolism. In this study we have analyzed intracellular diacylglycerol (DAG), a second messenger and an endogenous activator of protein kinase C. in unstimulated and agonist-stimulated neutrophils, from five LJP patients showing a chemotaxis defect and matched normal individuals. No difference was observed in the basal cellular DAG between the two groups. In neutrophils from LJP patients the DAG levels increased by 67% and 111% from the basal level following stimulation with N-formyl-methionyl-leucyl-phenylalanine (FMLP) and unopsonized zymosan particles, respectively, while in control cells the mean increases were 36% and 65%, respectively. Incubation with serum-opsonized zymosan particles produced an identical rise in DAG in both groups. These data indicate that the stimulation of receptors for FMLP and unopsonized zymosan may produce an enhanced accumulation of DAG in neutrophils from LJP patients. In addition to DAG mass analysis, we determined the effect of R59022, a DAG-kinase inhibitor, on zymosan-stimulated luminol-amplified chemiluminescence (CL) of neutrophils. In control cells R59022 significantly enhanced unopsonized zymosan induced CL, but it had no effect on cells from LJP patients, suggesting a possible change in the regulation of DAG-kinase in LJP. [ABSTRACT FROM AUTHOR]