Generation of specific deoxynojirimycin-type inhibitors of the non-lysosomal glucosylceramidase

The existence of a non-lysosomal glucosylceramidase in human cells has been documented (van Weely, S., Brandsma, M., Strijland, A., Tager, J. M., and Aerts, J. M. F. G. (1993) Biochim. Biophys. Acta 1181, 55-62). Hypothetically, the activity of this enzyme, which is localized near the cell surface, may influence ceramide-mediated signaling processes. To obtain insight in the physiological importance of the non-lysosomal glucosylceramidase, the availability of specific inhibitors would be helpful. Here we report on the generation of hydrophobic deoxynojirimycin (DNM) derivatives that potently inhibit the enzyme. The inhibitors were designed on the basis of the known features of the non-lysosomal glucosylceramidase and consist of a DNM moiety, an N-alkyl spacer, and a large hydrophobic group that promotes insertion in membranes. In particular, N-(5-adamantane-1-yl-methoxy)pentyl)-DNM is a very powerful inhibitor of the non-lysosomal glucosylceramidase at nanomolar concentrations. At such concentrations, the lysosomal glucocerebrosidase and alpha-glucosidase, the glucosylceramide synthase, and the N-linked glycan-trimming alpha-glucosidases of the endoplasmic reticulum are not affecte

Transglycosidase activity of chitotriosidase - Improved enzymatic assay for the human macrophage chitinase

Bio-organic Synthesi

Drinking on masculinity: Alcohol and gender in Andalusia

FWN – Publicaties zonder aanstelling Universiteit Leide

Hyperresponsiveness as a Determinant of the Outcome in Chronic Obstructive Pulmonary Disease

A better outcome of patients with chronic obstructive pulmonary disease (COPD) appears to be determined by higher FEV1, smoking cessation, lower airway hyperresponsiveness, and, at least in the presence of therapy, with a higher reversibility of airflow obstruction. In our opinion, these findings provide a firm ground for smoking cessation and most likely for institution of early treatment directed at both the reversible part of airflow obstruction and airway hyperresponsiveness in patients with COPD. But there are large gaps in our understanding of the effects of bronchodilator and antiinflammatory drugs on airway hyperresponsiveness. After acute administration, sympathomimetics cause a larger reduction of airway hyperresponsiveness than do anticholinergics, both in asthma and in COPD. What happens after longer periods of treatment is not yet clear in COPD, whereas in asthma there may occur a deterioration of airway responsiveness. Corticosteroids appear to have a beneficial effect on lung function and the severity of airway hyperresponsiveness in asthma. In COPD, however, no definite conclusion can be drawn as to the beneficial effect of corticosteroids, but short-term effects are not promising. The available data from the literature strongly suggest the need for long-term studies with large groups of patients in order to assess a potential treatment effect. In this way, also, a subgroup of patients with COPD who improve with corticosteroids and/or bronchodilators may be found. It seems advisable to include both subjective (i.e., quality of life, complaints, symptoms) and objective (i.e., hospitalization, survival, FEV1, PEFR, PC20, and reversibility) data as investigational tools for outcome analysis