Inhibition of LPS-induced iNOS and NO synthesis in primary rat microglial cells

Nitric oxide (NO) has been implicated in the etiopathology of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), and inhibition of NO synthesis has been proposed to be a possible mechanism of action of drugs to treat MS. In the present study, we investigated the inhibitory effect on NO synthesis of various steroids, cytokines and drugs used or proposed for the treatment of MS. As a model system, we used primary rat microglial cells which produce NO synthase and subsequently release NO upon stimulation with lipopolysaccharide (LPS). Among the substances tested, the glucocorticoids prednisone, hydrocortisone, dexamethasone and progesterone as well as transforming growth factor-beta (TGF-beta) dose-dependently inhibited LPS-induced nitric oxide synthase (iNOS) and NO synthesis. In contrast, COP-1, the phosphodiesterase inhibitors rolipram and pentoxifylline, the cytokines interleukin-10 (IL-10) and interferon-beta (IFN-beta) as well as the steroids beta-estradiol, testosterone, and dehydroepiandrosterone (DHEA) showed no inhibitory effect. Cholesterol slightly, but not significantly, increased LPS-induced nitric oxide synthesis. We conclude from the present study that with respect to treatment of MS, inhibition of NO synthesis may be an important mechanism of action of glucocorticoids and transforming growth factor-beta, but not of other drugs used or proposed to treat MS.     

Soil-transmitted helminth infections: updating the global picture

Public health workers and parasitologists have long been interested in estimating numbers infected with particular parasite species. Recent changes in social and economic conditions, in addition to implementation of control in some regions of the world, have changed the global picture of soil-transmitted helminth infections. This article brings global estimates up to date, reveals some interesting new trends and discusses the future for control.     

The effect of universal fluorinated nucleobases on the catalytic activity of ribozymes

Four fluoro modified universal nucleobases have been synthesized. The universal nucleobases 1 and 2, containing a 2,4-difluorobenzene as nucleobase and a 4,6-difluorobenzimidazole, respectively, were chemically incorporated into a selected hammerhead ribozyme sequence which has already been retrovirally expressed as an anti-HIV ribozyme to investigate their effect on the catalytic activity of the ribozymes. The substitution of the natural nucleosides with either 1 or 2 results only in a small decrease of the catalytic activity. The Km value for the monosubstituted ribozyme with a 2,4-difluorobenzene is 309 nM(-1), the corresponding kcat is 2.91 x 10(-3) min(-1). A disubstituted hammerhead ribozyme carrying one of each modification has also been synthesized. For a further stabilization of the ribozyme/substrate complex 2'-(beta-aminoethoxy) modified fluorinated nucleosides 15 and 16 have been developed.     

Doped natural phosphate: a new and environmentally friendly catalyst in nucleoside synthesis

Doped natural phosphate is used as acidic or basic catalyst in nucleoside and acyclonucleoside synthesis. Some examples are given.     

Helicobacter pylori does not mediate the formation of carcinogenic N-nitrosamines

Background. Both N‐nitroso compounds and colonization with Helicobacter pylori represent known risk‐factors for the development of gastric cancer. Endogenous formation of N‐nitroso compounds is thought to occur predominantly in acidic environments such as the stomach. At neutral pH, bacteria can catalyze the formation of N‐nitroso compounds. Based on experiments with a noncarcinogenic N‐nitroso compound as end product, and using only a single H. pylori strain, it was recently reported that H. pylori only displays a low nitrosation capacity. As H. pylori is a highly diverse bacterial species, it is reasonable to question the generality of this finding. In this study, several genetically distinct H. pylori strains are tested for their capacity to form carcinogenic N‐nitrosamines. Materials and Methods. Bacteria were grown in the presence of 0–1000 µM morpholine and nitrite (in a 1 : 1 molar ratio), at pH 7, 5 and 3. Results. Incubation of Neisseria cinerea (positive control) with 500 µM morpholine and 500 µM nitrite, resulted in a significant increase in formation of N‐nitrosomorpholine, but there was no significant induction of N‐nitrosomorpholine formation by any of the H. pylori strains, at any of the three pH conditions. Conclusion. H. pylori does not induce formation of the carcinogenic N‐nitrosomorpholine in vitro. The previously reported weak nitrosation capacity of H. pylori is not sufficient to nitrosate the more difficultly nitrosatable morpholine. This probably also holds true for other secondary amines. These results imply that the increased incidence of gastric cancer formation that is associated with gastric colonization by H. pylori is unlikely to result from the direct induced formation of carcinogenic nitrosamines by H. pylori. However, this has to be further confirmed in in vivo studies.     

Smoking status of parents, siblings and friends: predictors of regular smoking? Findings from a longitudinal twin-family study.

The relationship between regular smoking behavior and the smoking behavior of parents, siblings and friends was investigated using data from the Netherlands Twin Register. Cross-sectional analyses of data of 3906 twins showed significant associations between smoking behavior of the participant and smoking behavior of co-twin, additional brothers, parents of the same sex as the participant and friends. Those variables, together with age, explained 47% of the variance in smoking behavior. Longitudinal analyses of data from 2397 twins, who, in 1993, reported never to have smoked (regularly), showed that uptake of regular smoking two years later was predicted by having a smoking co-twin, smoking same-sex siblings, smoking mother and smoking friends. Males are, in contrast to females, at a later age still vulnerable to taking up regular smoking. The variables explained 21% of the variance. Sport participation, alcohol use, boredom susceptibility and neuroticism significantly added to the predictive value of this model. Including those additional factors increased the explained variance to 30%, and subsequently adding experimental smoking behavior further increased the explained variance to almost 50%. In summary, having smoking family members and friends, as well as lifestyle and personality factors are important predictors for the uptake of regular smoking. However, the experimental smoking behavior of the participant is equally important.