Plasmalogen content and beta-adrenoceptor signalling in fibroblasts from patients with Zellweger syndrome. Effects of hexadecylglycerol.

In Zellweger or cerebro-hepato-renal syndrome (CHRS), the assembly of peroxisomes is defective, resulting in deficient plasmalogen formation. Plasmalogens are part of the membrane lipid composition. In fibroblasts of CHRS patients, the plasmalogen fraction of phosphatidylethanolamine (PPE) was about half of that in control cells while total phospholipid (PL) content, individual PL and plasma membrane fluidity were normal. CHRS cell strains had higher beta-adrenoceptor numbers and isoproterenol-stimulated cAMP responses. Receptors were more efficiently coupled to adenylate cyclase than in control cells. Stimulations of cAMP with NaF or forskolin were the same as in control cells. Restoring synthesis of plasmalogens with hexadecylglycerol (HDG), a plasmalogen precursor, resulted in a proportionate increase in PPE of about 40% in both control and CHRS fibroblasts. Exposure to HDG reduced surface beta-adrenoceptor sites and cAMP-responses to isoproterenol in CHRS cells only, while post-receptor stimulations of cAMP were reduced in both cell types. Plasmalogen contents inversely correlated with isoproterenol-stimulated cAMP levels. The increased numbers of functional beta-adrenoceptors in CHRS fibroblasts may be the result of a higher expression and/or of a prolonged functional half-life of the receptor protein. In vivo, this may contribute to the clinical manifestations of the disease.

Biotin-dependent carboxylase activities in different CNS and skin-derived cells, and their sensitivity to biotin-depletion.

The validity of various transformed and untransformed CNS and skin-derived cell cultures as a model for studying effects of biotin deficiency was tested. In biotin-sufficient conditions (0.1-10 mumol/L) all cell types showed considerable activities of the four biotin-dependent carboxylases. Notably, pyruvate carboxylase activity was also present in the different neuronal cells. One passage in low-biotin medium (6-130 pmol/L) lowered mitochondrial carboxylase activities in all cell types, but to varying degrees. Sensitivity to biotin depletion was greatest in three neuronal cell types, Roc-1 oligodendroglia, and three keratinocyte cell types (carboxylase activities decreased to 2-11% of maximal); intermediate in primary astrocytes and C6 glioma (decreased to 12-28%), and least in SAOS2 sarcoma and skin fibroblasts (decreased to 32-85%). Transformed and untransformed cell lines of the same cell type showed similar sensitivity. We conclude that cultures of different transformed CNS and keratinocyte cell types allow the study of effects of biotin deprivation. Carboxylase activities of neurons, oligodendroglia, and keratinocytes were much more sensitive to biotin depletion than fibroblasts. This may be an important factor in the pathogenesis of neurological and cutaneous abnormalities in congenital biotinidase deficiency where recycling of biotin is deficient.

Anti-inflammatory activity of an extract of Petasites hybridus in allergic rhinitis.

Previous studies have suggested that histamine and leukotrienes (LTs) play an important pathobiological role in IgE-mediated allergic diseases. In vitro studies suggested that an extract of Petasites hybridus (Ze339) blocks LT synthesis in monocytes and granulocytes. Petasins are considered to be the pharmacologically active fraction within Ze339. Patients suffering from allergic rhinitis received three times a day two tablets of Ze339 standardized to 8 mg petasins within a time period of 1 week. After 5 days of treatment, Ze339 significantly improved primary end points, which were day- and nighttime nasal symptoms. Nasal resistance, which was measured by rhinomanometry, gradually decreased as a consequence of Ze339 treatment reaching normal levels after 5 days (rhinomanometry: from 403.5+/-62.0 to 844.8+/-38.8 ml). Levels of inflammatory mediators in nasal fluids and serum were measured 90 min after drug administration every day in the morning. After 5 days of treatment, a significant reduction of histamine (from 153.7+/-32.1 to 53.0+/-8.4 pg/ml) and LT levels (LTB4: from 313.1+/-46.5 to 180.6+/-32.2 pg/ml; cysteinyl-LT: from 137.0+/-42.2 to 70.1+/-16.5 pg/ml) could be observed. Moreover, quality-of-life scores significantly improved. The drug had no effect on the distribution of lymphocyte subpopulations in the blood as well as on the capacity of blood leukocytes to generate cytokines and lipid mediators. These results suggest that Ze339 is effective in treating allergic rhinitis patients by decreasing levels of nasal inflammatory mediators.